Database Query Results : , , eff

eff, efficacy: Click to Expand ⟱
Source:
Type:
Power to enhance an anti cancer effect
Scientific Papers found: Click to Expand⟱
2327- 2DG,    2-Deoxy-d-Glucose and Its Analogs: From Diagnostic to Therapeutic Agents
- Review, Var, NA
Glycolysis↓, 2-DG inhibits glycolysis due to formation and intracellular accumulation of 2-deoxy-d-glucose-6-phosphate (2-DG6P), inhibiting the function of hexokinase and glucose-6-phosphate isomerase, and inducing cell death
HK2↓,
mt-ROS↑, 2-DG-mediated glucose deprivation stimulates reactive oxygen species (ROS) production in mitochondria, also leading to AMPK activation and autophagy stimulation.
AMPK↑,
PPP↓, 2-DG has been shown to block the pentose phosphate shunt
NADPH↓, Decreased levels of NADPH correlate with reduced glutathione levels, one of the major cellular antioxidants.
GSH↓,
Bax:Bcl2↑, Valera et al. also observed that in bladder cancer cells, 2-DG treatment modulates the Bcl-2/Bax protein ratio, driving apoptosis induction
Apoptosis↑,
RadioS↑, 2-DG radiosensitization results from its effect on thiol metabolism
eff↓, (NAC) treatment, downregulated glutamate cysteine ligase activity, or overexpression of ROS scavenging enzymes
Half-Life↓, its plasma half-life was only 48 min [117]) make 2-DG a rather poor drug candidate
other↝, Adverse effects of 2-DG administration in humans include fatigue, sweating, dizziness, and nausea, mimicking the symptoms of hypoglycemia
eff↓, Moreover, 2-DG has to be used at relatively high concentrations (≥5 mmol/L) in order to compete with blood glucose

3972- ACNs,    Recent Research on the Health Benefits of Blueberries and Their Anthocyanins
- Review, AD, NA - Review, Park, NA
*cardioP↑, Epidemiological studies associate regular, moderate intake of blueberries and/or anthocyanins with reduced risk of cardiovascular disease, death, and type 2 diabetes, and with improved weight maintenance and neuroprotection.
*neuroP↑,
*Inflam↓, Among the more important healthful aspects of blueberries are their anti-inflammatory and antioxidant actions and their beneficial effects on vascular and glucoregulatory function
*antiOx↓,
*GutMicro↑, Blueberry phytochemicals may affect gastrointestinal microflora and contribute to host health
*Half-Life↑, However, >50% of the 13C still remained in the body after 48 h
*LDL↓, controlled study of 58 diabetic patients, blueberry intake led to a decline in LDL cholesterol, triglycerides, and adiponectin and an increase in HDL cholesterol
*adiP↓,
*HDL↑,
*CRP↓, reduction was documented in inflammatory markers, including serum high-sensitivity C-reactive protein, soluble vascular adhesion molecule-1, and plasma IL-1β
*IL1β↓,
*Risk↓, lower Parkinson disease risk was associated with the highest quintile of anthocyanin (RR: 0.76) and berry (RR: 0.77) intake
*Risk↓, Nurse's Health Study, greater intake of blueberries and strawberries was associated with slower rates of cognitive decline in older adults, with an estimated delay in decline of about 2.5 y
*cognitive↑, Cognitive performance in elderly adults improved after 12 wk of daily intake of blueberry (94) or Concord grape (95) juice.
*memory↑, Better task switching and reduced interference in memory was found in healthy older adults after 90 d of blueberry supplementation
*other↑, After 12 wk of blueberry consumption, greater brain activity was detected using magnetic resonance imaging in healthy older adults during a cognitive challenge.
*BOLD↑, Similarly, during a memory test, regional blood oxygen level-dependent activity detected by MRI (99) was enhanced in the subjects taking blueberry, but not in those taking placebo.
*NO↓, 50–200 mg/d bilberry showed a dose-dependent decrease in neurotoxic NO and malondialdehyde, combined with an increase in neuroprotective antioxidant capacity due to glutathione, vitamin C, superoxide dismutase, and glutathione peroxidase
*MDA↓,
*GSH↑,
*VitC↑,
*SOD↑,
*GPx↑,
*eff↓, The percentage loss of blueberry anthocyanins during −18°C storage was 12% after 10 mo of storage
*eff↓, Freeze-dried blueberry powder loses anthocyanins in a temperature-dependent manner with a half-life of 139, 39, and 12 d when stored at 25, 42, and 60°C, respectively
*eff↓, Blueberries are low in ascorbic acid and high in anthocyanins (187), and notably anthocyanins are readily degraded by ascorbic acid
*eff↝, Shelf-stable blueberry products like jam (196), juice (197), and extracts (198) can lose polyphenolic compounds when stored at ambient temperature whereas refrigeration mitigates losses.
*Risk↓, It can be safely stated that daily moderate intake (50 mg anthocyanins, one-third cup of blueberries) can mitigate the risk of diseases and conditions of major socioeconomic importance in the Western world.

234- AL,    Allicin Induces Anti-human Liver Cancer Cells through the p53 Gene Modulating Apoptosis and Autophagy
- in-vitro, HCC, Hep3B
ROS↑, increased the production of ROS levels at 1, 3, 6 h. I
*toxicity∅, In other study, allicin treatment did not increase the leakage of lactate-dehydrogenase (LDH) of primary rat hepatocytes until 1 mM allicin treated with rat hepatocytes24. For this reason, allicin could be inferred as safe to normal liver cells
MMP↓, Allicin decreased mitochondrial membrane potential
BAX↑,
Bcl-2↓,
AIF↑,
Casp3↑, protein expression levels of caspase-3, -8, -9 increased after allicin treatment
Casp8↑,
Casp9↑,
eff↓, Allicin significantly induced ROS overproduction, whereas NAC pretreatment decreased the ROS induction by allicin exposure in Hep 3B cells
γH2AX↑, significant increase in the expression of γ-H2AX was observed at the initial stages (3, 6 h), but not at the later stages of 12, 24, 48 h
selectivity↑, data suggested that allicin induced apoptosis in p53-deficiency human liver carcinoma cells but caused autophagy in p53-normal function human liver carcinoma cells.
DNA-PK↑, increases production of ROS, triggers DNA damage

235- AL,    Allicin inhibits cell growth and induces apoptosis in U87MG human glioblastoma cells through an ERK-dependent pathway
- in-vitro, GBM, U87MG
Apoptosis↑,
Bcl-2↓,
BAX↑,
MAPK↑, mechanisms involved in apoptosis include the mitochondrial pathway, activation of mitogen-activated protein kinases (MAPKs), and caspase cascade and oxidant enzyme system.
p‑ERK↑, In the present study, the level of ERK phosphorylation was increased
ROS↑, ROS are related to allicin-induced apoptosis in the U87MG cells.
eff↓, This study demonstrated that allicin-induced apoptosis was down-regulated by the antioxidant enzyme system

1916- AL,    Allicin Bioavailability and Bioequivalence from Garlic Supplements and Garlic Foods
- Review, Nor, NA
*BioAv↝, For enteric tablets, ABB varied from 36–104%
*eff↓, but it was reduced to 22–57% when consumed with a high-protein meal, due to slower gastric emptying.
*BioAv↝, garlic powder capsules gave 26–109%
*BioAv↝, Kwai garlic powder tablets, which have been used in a large number of clinical trials, gave 80% ABB, validating it as representing raw garlic in those trials
*eff↑, Hence, many brands of garlic supplements have been enteric-coated to prevent disintegration in the stomach
*Half-Life∅, Hence, many brands of garlic supplements have been enteric-coated to prevent disintegration in the stomach
*eff↑, all brands of normal tablets gave high allicin bioavailability
*eff↑, Hence, both low-protein and high-protein meals would provide a gastric pH ≥ 4.0 for an ample amount of time for the alliinase in disintegrated normal tablets and capsules to convert most of the alliin to allicin in the stomach.
*Dose∅, Three tablets has been the most common dose used in these trials. The N1 tablets in these trials have been consistently standardized to contain 3.9 mg alliin/tablet and to yield 1.8 mg allicin/tablet
*eff↑, The bioavailability of allicin from garlic powder supplements containing alliin and active alliinase can be as high as that from an equivalent amount of crushed raw garlic containing maximum allicin, when consumed with a meal.

2646- AL,    Anti-Cancer Potential of Homemade Fresh Garlic Extract Is Related to Increased Endoplasmic Reticulum Stress
- in-vitro, Pca, DU145 - in-vitro, Melanoma, RPMI-8226
AntiCan↑, simple homemade ethanol-based garlic extract (GE). We show that GE inhibits growth of several different cancer cells in vitro
eff↓, These activities were lost during freeze or vacuum drying, suggesting that the main anti-cancer compounds in GE are volatile.
ChemoSen↑, We found that GE enhanced the activities of chemotherapeutics
ER Stress↑, Our data indicate that the reduced proliferation of the cancer cells treated by GE is at least partly mediated by increased endoplasmic reticulum (ER) stress.
tumCV↓, homemade GE was found to reduce the viability of the two multiple myeloma (MM) cell lines, RPMI-8226 and JJN3, as well as the prostate cancer cell line DU145 in a dose-dependent manner,
DNAdam↑, GE alone slightly increased the percentage of tail DNA (% Tail) (representing cumulative levels of abasic sites, as well as single- and double-strand DNA breaks) measured at day one, compared to untreated cells
GSH∅, We could not detect any changes in cellular GSH levels after treatments with GE
HSP70/HSPA5↓, ; however, in support of increased ER stress after GE treatment, we detected an increased pulldown of HSPA5 (BIP), a member of the Hsp70 family
UPR↑, s leading to the accumulation of unfolded proteins in the ER (also known as GRP78)
β-catenin/ZEB1↓, we also found a reduction in the β-catenin leve
ROS↑, In further support for increased ER stress induced by GE, which will lead to elevated ROS-levels and oxidative stress
HO-2↑, we found a significant increase in proteins activated by and important for regulating cellular ROS levels, e.g., OXR1, Txnl1, Hmox2, and Sirt1
SIRT1↑,
GlucoseCon∅, glucose consumption, as well as lactate secretion, were not changed.
lactateProd∅,
chemoP↑, Garlic is reported to reduce cisplatin-induced nephrotoxicity and oxidative stress

281- ALA,    Reactive oxygen species mediate caspase activation and apoptosis induced by lipoic acid in human lung epithelial cancer cells through Bcl-2 down-regulation
- in-vitro, Lung, H460
mt-ROS↑, mitochondria are the primary source of ROS production induced by LA and that these ROS are involved in the apoptotic process.
Apoptosis↑,
Casp9↑,
Bcl-2↓,
eff↓, that all the tested antioxidants were able to inhibit apoptosis induced by LA or DHLA indicating that multiple ROS are involved in the apoptotic process.
eff↑, The pro-oxidant role of LA is generally observed under nonoxidative stress conditions, which is also supported by this study
H2O2↑, LA also induced peroxide generation in these cells
Dose↑, 100uM was enough to generate mitochondrial ROS in lung cancer cells

3454- ALA,    Lipoic acid blocks autophagic flux and impairs cellular bioenergetics in breast cancer and reduces stemness
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
TumCG↑, Lipoic acid inhibits breast cancer cell growth via accumulation of autophagosomes.
Glycolysis↓, Lipoic acid inhibits glycolysis in breast cancer cells.
ROS↑, Lipoic acid induces ROS production in breast cancer cells/BCSC.
CSCs↓, Here, we demonstrate that LA inhibits mammosphere formation and subpopulation of BCSCs
selectivity↑, In contrast, LA at similar doses. had no significant effect on the cell viability of the human embryonic kidney cell line (HEK-293)
LC3B-II↑, LA treatment (0.5 mM and 1.0 mM) increased the expression level of LC3B-I to LC3B-II in both MCF-7 and MDA-MB231cells at 48 h
MMP↓, LA induced mitochondrial ROS levels, decreased mitochondria complex I activity, and MMP in both MCF-7 and MDA-MB231 cells
mitResp↓, In MCF-7 cells, we found a substantial reduction in maximal respiration and ATP production at 0.5 mM and 1 mM of LA treatment after 48 h
ATP↓,
OCR↓, LA at 2.5 mM decreased OCR
NAD↓, we found that LA (0.5 mM and 1 mM) significantly reduced ATP production and NAD levels in MCF-7 and MDA-MB231 cells
p‑AMPK↑, LA treatment (0.5 mM and 1.0 mM) increased p-AMPK levels;
GlucoseCon↓, LA (0.5 mM and 1 mM) significantly decreased glucose uptake and lactate production in MCF-7, whereas LA at 1 mM significantly reduced glucose uptake and lactate production in MDA-MB231 cells but it had no effect at 0.5 mM
lactateProd↓,
HK2↓, LA reduced hexokinase 2 (HK2), phosphofructokinase (PFK), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA) expression in MCF-7 and MDA-MB231 cells
PFK↓,
LDHA↓,
eff↓, Moreover, we found that LA-mediated inhibition of cellular bioenergetics including OCR (maximal respiration and ATP production) and glycolysis were restored by NAC treatment (Fig. 6E and F) which indicates that LA-induced ROS production is responsibl
mTOR↓, LA inhibits mTOR signaling and thereby decreased the p-TFEB levels in breast cancer cells
ECAR↓, LA also inhibits glycolysis as evidenced by decreased glucose uptake, lactate production, and ECAR.
ALDH↓, LA decreased ALDH1 activity, CD44+/CD24-subpopulation, and increased accumulation of autophagosomes possibly due to inhibition of autophagic flux of breast cancer.
CD44↓,
CD24↓,

3272- ALA,    Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential
- Review, AD, NA
*antiOx↑, LA has long been touted as an antioxidant,
*glucose↑, improve glucose and ascorbate handling,
*eNOS↑, increase eNOS activity, activate Phase II detoxification via the transcription factor Nrf2, and lower expression of MMP-9 and VCAM-1 through repression of NF-kappa-B.
*NRF2↑,
*MMP9↓,
*VCAM-1↓,
*NF-kB↓,
*cardioP↑, used to improve age-associated cardiovascular, cognitive, and neuromuscular deficits,
*cognitive↑,
*eff↓, The efficiency of LA uptake was also lowered by its administration in food,
*BBB↑, LA has been shown to cross the blood-brain barrier in a limited number of studies;
*IronCh↑, LA preferentially binds to Cu2+, Zn2+ and Pb2+, but cannot chelate Fe3+, while DHLA forms complexes with Cu2+, Zn2+, Pb2+, Hg2+ and Fe3+
*GSH↑, LA markedly increases intracellular glutathione (GSH),
*PKCδ↑, PKCδ, LA activates Erk1/2 [92,93], p38 MAPK [94], PI3 kinase [94], and Akt
*ERK↑,
*p38↑,
*MAPK↑,
*PI3K↑,
*Akt↑,
*PTEN↓, LA decreases the activities of Protein Tyrosine Phosphatase 1B [99], Protein Phosphatase 2A [95], and the phosphatase and tensin homolog PTEN [95],
*AMPK↑, LA activates peripheral AMPK
*GLUT4↑, stimulate GLUT4 translocation
*GLUT1↑, LA-stimulated translocation of GLUT1 and GLUT4.
*Inflam↓, LA as an anti-inflammatory agent

1440- AMQ,    Lysosomotropism depends on glucose: a chloroquine resistance mechanism
- in-vitro, BC, 4T1
eff↑, Importantly, we found that the related compound, amodiaquine, was more potent than CQ for cell killing and not susceptible to interference from glucose starvation.
Apoptosis↓,
Necroptosis↑,
eff↓, Unexpectedly, further withdrawal of glucose, in the context of serum starvation, fully rescued the effect of CQ
ChemoSen↑, CQ markedly enhanced the sensitivity of 4T1 cells to doxorubicin
eff↓, Inhibition of glycolysis with 2DG also rescued cells from CQ.

1354- And,    Andrographolide induces protective autophagy and targeting DJ-1 triggers reactive oxygen species-induced cell death in pancreatic cancer
- in-vitro, PC, NA - in-vivo, PC, NA
Apoptosis↑,
DJ-1↓, reduction in DJ-1 expression caused by Andro led to ROS accumulation
ROS↑,
TumAuto↑,
TumCCA↑, G2/M phase
TumCP↓,
TumW↓,
eff↓, pro-apoptotic effect of Andro was attenuated when NAC was co-administered

1536- Api,    Apigenin causes necroptosis by inducing ROS accumulation, mitochondrial dysfunction, and ATP depletion in malignant mesothelioma cells
- in-vitro, MM, MSTO-211H - in-vitro, MM, H2452
tumCV↓,
ROS↑, increase in intracellular reactive oxygen species (ROS)
MMP↓, caused the loss of mitochondrial membrane potential (ΔΨm)
ATP↓, ATP depletion
Apoptosis↑,
Necroptosis↑,
DNAdam↑,
TumCCA↑, delay at the G2/M phase of cell cycle
Casp3↑,
cl‑PARP↑,
MLKL↑,
p‑RIP3↑,
Bax:Bcl2↑,
eff↓, ATP supplementation restored cell viability and levels of DNA damage-, apoptosis- and necroptosis-related proteins that apigenin caused.
eff↓, N-acetylcysteine reduced ROS production and improved ΔΨm loss and cell death that were caused by apigenin.

1564- Api,    Apigenin-induced prostate cancer cell death is initiated by reactive oxygen species and p53 activation
- in-vitro, Pca, 22Rv1 - in-vivo, NA, NA
MDM2↓, downregulation of MDM2 protein
NF-kB↓, Exposure of 22Rv1 cells to 20 μM apigenin caused a decrease in NF-κB/p65 transcriptional activity by 24% at 12 h, which was further decreased to 41% at 24 h
p65↓,
P21↑,
ROS↑, Apigenin at these doses resulted in ROS generation
GSH↓, which was accompanied by rapid glutathione depletion
MMP↓, disruption of mitochondrial membrane potential
Cyt‑c↑, cytosolic release of cytochrome c
Apoptosis↑,
P53↑, accumulation of a p53 fraction to the mitochondria, which was rapid and occurred between 1 and 3 h after apigenin treatment
eff↓, All these effects were significantly blocked by pretreatment of cells with the antioxidant N-acetylcysteine
Bcl-xL↓,
Bcl-2↓,
BAX↑,
Casp↑, triggering caspase activation
TumCG↓, in vivo mice
TumVol↓, tumor volume was inhibited by 44 and 59%
TumW↓, wet weight of tumor was decreased by 41 and 53%

1563- Api,  MET,    Metformin-induced ROS upregulation as amplified by apigenin causes profound anticancer activity while sparing normal cells
- in-vitro, Nor, HDFa - in-vitro, PC, AsPC-1 - in-vitro, PC, MIA PaCa-2 - in-vitro, Pca, DU145 - in-vitro, Pca, LNCaP - in-vivo, NA, NA
selectivity↑, Metformin increased cellular ROS levels in AsPC-1 pancreatic cancer cells, with minimal effect in HDF, human primary dermal fibroblasts.
selectivity↑, Metformin reduced cellular ATP levels in HDF, but not in AsPC-1 cells
selectivity↓, Metformin increased AMPK, p-AMPK (Thr172), FOXO3a, p-FOXO3a (Ser413), and MnSOD levels in HDF, but not in AsPC-1 cells
ROS↑,
eff↑, Metformin combined with apigenin increased ROS levels dramatically and decreased cell viability in various cancer cells including AsPC-1 cells, with each drug used singly having a minimal effect.
tumCV↓,
MMP↓, Metformin/apigenin combination synergistically decreased mitochondrial membrane potential in AsPC-1 cells but to a lesser extent in HDF cells
Dose∅, co-treatment with metformin (0.05, 0.5 or 5 mM) and apigenin (20 µM) dramatically increased cellular ROS levels in AsPC-1 cells
eff↓, NAC blocked the metformin/apigenin co-treatment-induced cell death in AsPC-1 cells
DNAdam↑, Combination of metformin and apigenin leads to DNA damage-induced apoptosis, autophagy and necroptosis in AsPC-1 cells but not in HDF cells
Apoptosis↑,
TumAuto↑,
Necroptosis↑,
p‑P53↑, p-p53, Bim, Bid, Bax, cleaved PARP, caspase 3, caspase 8, and caspase 9 were also significantly increased by combination of metformin and apigenin in AsPC-1
BIM↑,
BAX↑,
p‑PARP↑,
Casp3↑,
Casp8↑,
Casp9↑,
Cyt‑c↑, Cytochrome C was also released from mitochondria in AsPC-1 cell
Bcl-2↓,
AIF↑, Interestingly, autophagy-related proteins (AIF, P62 and LC3B) and necroptosis-related proteins (MLKL, p-MLKL, RIP3 and p-RIP3) were also increased by combination of metformin and apigenin
p62↑,
LC3B↑,
MLKL↑,
p‑MLKL↓,
RIP3↑,
p‑RIP3↑,
TumCG↑, in vivo
TumW↓, metformin (125 mg/kg) or apigenin (40 mg/kg) caused a reduction of tumor size compared to the control group (Fig. 7D). However, oral administration of combination of metformin and apigenin decreased tumor weight profoundly

3391- ART/DHA,    Antitumor Activity of Artemisinin and Its Derivatives: From a Well-Known Antimalarial Agent to a Potential Anticancer Drug
- Review, Var, NA
TumCP↓, inhibiting cancer proliferation, metastasis, and angiogenesis.
TumMeta↓,
angioG↓,
TumVol↓, reduces tumor volume and progression
BioAv↓, artemisinin has low solubility in water or oil, poor bioavailability, and a short half-life in vivo (~2.5 h)
Half-Life↓,
BioAv↑, semisynthetic derivatives of artemisinin such as artesunate, arteeter, artemether, and artemisone have been effectively used as antimalarials with good clinical efficacy and tolerability
eff↑, preloading of cancer cells with iron or iron-saturated holotransferrin (diferric transferrin) triggers artemisinin cytotoxicity
eff↓, Similarly, treatment with desferroxamine (DFO), an iron chelator, renders compounds inactive
ROS↑, ROS generation may contribute with the selective action of artemisinin on cancer cells.
selectivity↑, Tumor cells have enhanced vulnerability to ROS damage as they exhibit lower expression of antioxidant enzymes such as superoxide dismutase, catalase, and gluthatione peroxidase compared to that of normal cells
TumCCA↑, G2/M, decreased survivin
survivin↓,
BAX↑, Increased Bax, activation of caspase 3,8,9 Decreased Bc12, Cdc25B, cyclin B1, NF-κB
Casp3↓,
Casp8↑,
Casp9↑,
CDC25↓,
CycB↓,
NF-kB↓,
cycD1↓, decreased cyclin D, E, CDK2-4, E2F1 Increased Cip 1/p21, Kip 1/p27
cycE↓,
E2Fs↓,
P21↑,
p27↑,
ADP:ATP↑, Increased poly ADP-ribose polymerase Decreased MDM2
MDM2↓,
VEGF↓, Decreased VEGF
IL8↓, Decreased NF-κB DNA binding [74, 76] IL-8, COX2, MMP9
COX2↓,
MMP9↓,
ER Stress↓, ER stress, degradation of c-MYC
cMyc↓,
GRP78/BiP↑, Increased GRP78
DNAdam↑, DNA damage
AP-1↓, Decreased NF-κB, AP-1, Decreased activation of MMP2, MMP9, Decreased PKC α/Raf/ERK and JNK
MMP2↓,
PKCδ↓,
Raf↓,
ERK↓,
JNK↓,
PCNA↓, G2, decreased PCNA, cyclin B1, D1, E1 [82] CDK2-4, E2F1, DNA-PK, DNA-topo1, JNK VEGF
CDK2↓,
CDK4↓,
TOP2↓, Inhibition of topoisomerase II a
uPA↓, Decreased MMP2, transactivation of AP-1 [56, 88] NF-κB uPA promoter [88] MMP7
MMP7↓,
TIMP2↑, Increased TIMP2, Cdc42, E cadherin
Cdc42↑,
E-cadherin↑,

2580- ART/DHA,  VitC,    Effects of Antioxidants and Pro-oxidants on Cytotoxicity of Dihydroartemisinin to Molt-4 Human Leukemia Cells
- in-vitro, AML, NA
eff↓, Compared to control, ascorbate and H 2 O 2 both caused a significant decrease in cell count both at 24-h (p<0.05 and p<0.0001 for ascorbate and H 2 O 2 , respectively)
other↝, Vitamin C, a common supplement, has been shown to act as both a ROS generator in the presence of iron and copper (15) and as an antioxidant
ROS↑, From our results, we can postulate that ROS generation is causing cell death independently and in combination with DHA
eff↓, Ascorbate can convert ferric iron into ferrous iron (18), the active form that reacts with artemisinin, generating short lived free radicals.
eff↓, If this happens in the stomach of a person who is consuming artemisinin along with ascorbate, ascorbate will convert ferric iron in foods to the ferrous form, which may react with artemisinin locally, making the therapy less effective

1370- Ash,    Withaferin A induces mitochondrial-dependent apoptosis in non-small cell lung cancer cells via generation of reactive oxygen species
- in-vitro, Lung, A549
ROS↑,
eff↓, while the non-carcinoma cells WI-38 and PBMC were unaffected.

1365- Ash,    Withaferin A Induces Oxidative Stress-Mediated Apoptosis and DNA Damage in Oral Cancer Cells
- in-vitro, Oral, Ca9-22 - in-vitro, Oral, CAL27
ROS↑, Withaferin A (WFA) is one of the most active steroidal lactones with reactive oxygen species (ROS) modulating effects against several types of cancer.
*toxicity↓, killed two oral cancer cells (Ca9-22 and CAL 27) rather than normal oral cells (HGF-1) HGF-1 normal oral cells treated with WFA showed no reduction in viability
Apoptosis↑,
TumCCA↑, G2/M cell cycle arrest
MMP↓,
p‑γH2AX↑,
DNAdam↑,
eff↓, Moreover, pretreating Ca9-22 cells with N-acetylcysteine (NAC) rescued WFA-induced selective killing

1364- Ash,    Withaferin a Triggers Apoptosis and DNA Damage in Bladder Cancer J82 Cells through Oxidative Stress
- in-vitro, Bladder, J82
cl‑Casp3↑,
cl‑Casp8↑,
cl‑Casp9↑,
cl‑PARP↑,
ROS↑,
MMP↓,
DNAdam↑,
eff↓, ROS scavenger N-acetylcysteine reverts all tested WFA-modulating effects.

1361- Ash,  SRF,    Withaferin A, a natural thioredoxin reductase 1 (TrxR1) inhibitor, synergistically enhances the antitumor efficacy of sorafenib through ROS-mediated ER stress and DNA damage in hepatocellular carcinoma cells
- in-vitro, Liver, HUH7 - in-vivo, Liver, HUH7
TrxR↓, TrxR1
ROS↑,
DNA-PK↑,
ER Stress↑,
Apoptosis↑,
eff↓, Pre-treatment with the antioxidant NAC significantly inhibited ROS generation, ER stress, DNA damage, and apoptosis induced by Sora/WA co-treatment

1360- Ash,  immuno,    Withaferin A Increases the Effectiveness of Immune Checkpoint Blocker for the Treatment of Non-Small Cell Lung Cancer
- in-vitro, Lung, H1650 - in-vitro, Lung, A549 - in-vitro, CRC, HCT116 - in-vitro, BC, MDA-MB-231 - in-vivo, NA, NA
PD-L1↑,
eff↓, The administration of N-acetyl cysteine (NAC), a reactive oxygen species (ROS) scavenger, abrogated WFA-induced ICD and PD-L1 upregulation, suggesting the involvement of ROS in this process.
ROS↑,
ER Stress↑,
Apoptosis↑,
BAX↑,
Bak↑,
BAD↑,
Bcl-2↓,
XIAP↓,
survivin↓,
cl‑PARP↑,
CHOP↑,
p‑eIF2α↑, phosphorylation of the eukaryotic initiation factor eIF-2
ICD↑,
eff↑, WFA Sensitizes LLC Syngeneic Mouse Tumors to α-PD-L1 In Vivo

1369- Ash,    Withaferin A inhibits cell proliferation of U266B1 and IM-9 human myeloma cells by inducing intrinsic apoptosis
- in-vitro, Melanoma, U266
tumCV↓,
Apoptosis↑,
BAX↑,
Cyt‑c↑,
Bcl-2↓,
cl‑PARP↑,
cl‑Casp3↑,
cl‑Casp9↑,
ROS↑,
eff↓, treatment of the U266B1 and IM-9 with ascorbic acid (antioxidant) could prevent the withaferin A mediated ROS production and the withaferin A induced antiproliferative effects.

1357- Ash,    Cytotoxicity of withaferin A in glioblastomas involves induction of an oxidative stress-mediated heat shock response while altering Akt/mTOR and MAPK signaling pathways
- in-vitro, GBM, U87MG - in-vitro, GBM, U251 - in-vitro, GBM, GL26
TumCP↓,
TumCCA↑, G2/M cell cycle
Akt↓,
mTOR↓,
p70S6↓,
p85S6K↓,
AMPKα↑,
TSC2↑,
HSP70/HSPA5↑,
HO-1↑,
HSF1↓,
Apoptosis↑,
ROS↑, Withaferin A elevates pro-oxidant potential in GBM cells and induces a cellular oxidative stress response
eff↓, Pre-treatment with a thiol-antioxidant protects GBM cells from the anti-proliferative and cytotoxic effects of withaferin A NAC pretreatment was able to completely prevent cell cycle shift to G2/M arrest following 1µM WA treatment at 24h

1373- Ash,    Endoplasmic reticulum stress mediates withaferin A-induced apoptosis in human renal carcinoma cells
- in-vitro, Kidney, Caki-1
ER Stress↑,
p‑eIF2α↑,
XBP-1↑,
GRP78/BiP↑,
CHOP↑,
eff↓, Pretreatment with N-acetyl cysteine (NAC) significantly inhibited withaferin A-mediated ER stress proteins and cell death, suggesting that reactive oxygen species (ROS) mediate withaferin A-induced ER stress.

1371- Ash,    Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic cell death of human myeloid leukemia HL-60 cells by a dietary compound withaferin A with concomitant protection by N-acetyl cysteine
- in-vitro, AML, HL-60
ROS↑,
MMP↓,
cl‑Casp3↑,
cl‑Casp9↑,
cl‑PARP↑,
eff↓, N-acetyl-cysteine rescued all these events suggesting thereby a pro-oxidant effect of withaferinA.

1142- Ash,    Ashwagandha-Induced Programmed Cell Death in the Treatment of Breast Cancer
- Review, BC, MCF-7 - NA, BC, MDA-MB-231 - NA, Nor, HMEC
Apoptosis↑,
ROS↑, anti-cancer effect of WA was significantly attenuated in the presence of anti-oxidants,
DNAdam↑,
OXPHOS↓, WA inhibits oxidative phosphorylation (OXPHOS) in Complex III, accompanied by apoptotic release of DNA fragments associated with histones in the cytosol
*ROS∅, WA shows high selectivity, causing ROS production only in MDA-MB-231 and MCF-7 cells, but not in the normal human mammary epithelial cell line (HMEC)
Bcl-2↓,
XIAP↓,
survivin↓,
DR5↑,
IKKα↓,
NF-kB↓,
selectivity↑, Moreover, WA shows high selectivity, causing ROS production only in MDA-MB-231 and MCF-7 cells, but not in the normal human mammary epithelial cell line (HMEC)
*ROS∅, Moreover, WA shows high selectivity, causing ROS production only in MDA-MB-231 and MCF-7 cells, but not in the normal human mammary epithelial cell line (HMEC)
eff↓, the anti-cancer effect of WA was significantly attenuated in the presence of anti-oxidants, as it has been shown that ectopic expression of Cu and Zn-superoxide dismutase (SOD) significantly weakens its apoptotic properties
Paraptosis↑, WA promotes death in both MCF-7 and MDA-MB-231 cell lines through paraptosis through the action of ROS

1533- Ba,    Baicalein, as a Prooxidant, Triggers Mitochondrial Apoptosis in MCF-7 Human Breast Cancer Cells Through Mobilization of Intracellular Copper and Reactive Oxygen Species Generation
- in-vitro, BrCC, MCF-7 - in-vitro, Nor, MCF10
tumCV↓,
i-ROS↑, enhancement the level of intracellular ROS exhibit pro-oxidant activity in the presence of copper ions
MMP↓,
Bcl-2↓,
BAX↑,
Cyt‑c↑, release of cytochrome C
Casp9↑,
Casp3↑,
eff↓, The pretreatment with NeoCu (I)-specific chelator) remarkably weakened these effects of baicalein exhibit pro-oxidant activity in the presence of copper ions
selectivity↑, baicalein presented little cytotoxicity to normal breast epithelial cells
*toxicity∅, baicalein presented little cytotoxicity to normal breast epithelial cells. explained by the undetectable levels of copper present in MCF-10A cells.
Apoptosis↑,
Fenton↑, results are in further support that the prooxidant action of baicalein involves the reduction of Cu (II) to Cu (I), and the consequent generation of hydroxyl radicals.

1520- Ba,    Baicalein Induces G2/M Cell Cycle Arrest Associated with ROS Generation and CHK2 Activation in Highly Invasive Human Ovarian Cancer Cells
- in-vitro, Ovarian, SKOV3 - in-vitro, Ovarian, TOV-21G
TumCG↓,
TumCCA↑, G2/M phase
ROS↑, Baicalein-induced G2/M phase arrest is associated with an increased reactive oxygen species (ROS) production, DNA damage, and CHK2 upregulation and activation
DNAdam↑,
Chk2↑,
Dose∅, produced significant ROS in a dose- and time-dependent manner in SKOV-3 cells
p‑γH2AX↑, baicalein treatment increased the phosphorylation of H2AX (γH2AX)
CDC25↓,
CHK1↓,
cycD1↓,
eff↓, CHK2 inhibitor indeed reduced the extent of CHK2 phosphorylation (Figure 4A) and protected SKOV-3 cells from baicalein-mediated G2/M arrest (Fig
12LOX↓, the pro-oxidative effect of baicalein, a specific inhibitor of 12-LOX, on ovarian cancer cells may occur through inhibiting the activity of 12-LOX, thereby inducing the accumulation of hydroxyl radicals.

1521- Ba,    Baicalein induces apoptosis via ROS-dependent activation of caspases in human bladder cancer 5637 cells
- in-vitro, Bladder, 5637
TumCG↓,
Apoptosis↑,
IAP1↓, downregulation of members of the inhibitor of apoptosis protein (IAP) family, including cIAP-1 and cIAP-2,
IAP2↓,
Casp3↑, activation of caspase-9 and -3
Casp9↑,
BAX↑,
Bcl-2↓,
MMP↓, dose-dependent loss of MMP
Casp8↑,
BID↑,
ROS?, baicalein can induce the production of reactive oxygen species (ROS) hese findings suggest that an increase in ROS is required for the occurrence of baicalein- induced apoptosis in 5637 cells.
eff↓, pretreatment with the antioxidant N-acetyl-L-cysteine significantly attenuates the baicalein effects on the loss of MMP and activation of caspase
DR4↑, baicalein considerably increased the levels of DR4, DR5, FasL, and TRAIL.
DR5↑,
FasL↑,
TRAIL↑,

1523- Ba,    Baicalein induces human osteosarcoma cell line MG-63 apoptosis via ROS-induced BNIP3 expression
- in-vitro, OS, MG63 - in-vitro, Nor, hFOB1.19
TumCD↑,
Apoptosis↑,
ROS↑, baicalein activated apoptosis through induced intracellular reactive oxygen species (ROS) generation
eff↓, and that ROS scavenger N-acetyl-cysteine (NAC), glutathione (GSH), and superoxide dismutase (SOD) apparently inhibited intracellular ROS production, consequently attenuating the baicalein-induced apoptosis.
Casp3↑, Baicalein treatment markedly increased active caspase-3 expression
Bcl-2↓,
selectivity↑, baicalein influenced little growth reduction of hFOB1.19 cells. (normal cells)
Cyt‑c↑, release of cytochrome c from mitochondrial to cytosol
LDH?, (25 and 50 μM) induced increases of LDH release (2.2- and 3.6-folds) which showed the cytotoxicity of baicalein
BNIP3?, we conclude that baicalein induces ROS production and BNIP3 expression with the subsequent activation of Bax
BAX↑,

1524- Ba,    Baicalein Induces Caspase‐dependent Apoptosis Associated with the Generation of ROS and the Activation of AMPK in Human Lung Carcinoma A549 Cells
- in-vitro, Lung, A549
DR5↑, Baicalein stimulated the expression of DR5, FasL, and FADD, and activated caspase‐8
FADD↑,
FasL↑,
Casp8↑,
cFLIP↓, reducing the levels of FLIPs
Casp3↑, activation of caspase‐9 and −3, and cleavage of poly(ADP‐ribose) polymerase
Casp9↑,
cl‑PARP↑,
MMP↓, baicalein caused a mitochondrial membrane potential (MMP),
BID↑, the truncation of Bid (means that the protein has been converted into an active form (tBid) that supports apoptosis.)
Cyt‑c↑, inducing the release of cytochrome c into the cytosol
ROS↑, baicalein increased the generation of reactive oxygen species (ROS)
eff↓, however, an ROS scavenger, N‐acetylcysteine, notably attenuated baicalein‐mediated loss of MMP and activation of caspases
AMPK↑,
Apoptosis↑,
TumCCA↑, sub-G1 phase
DR5↑, baicalein increased the expression of DR5 and FasL in a concentration-dependent manner, whereas the levels of DR4
FasL↑,
DR4∅,
cFLIP↓, baicalein reduced both FLIP(L) and FLIP(S) protein levels
FADD↑, increased FADD expression
MMPs↓, baicalein treatment reduced MMP levels in a concentrationdependent manner

1525- Ba,  almon,    Synergistic antitumor activity of baicalein combined with almonertinib in almonertinib-resistant non-small cell lung cancer cells through the reactive oxygen species-mediated PI3K/Akt pathway
- in-vitro, Lung, H1975 - in-vivo, Lung, NA
eff↑, Compared with baicalein or almonertinib alone, the combined application of the two drugs dramatically attenuates cell proliferation
TumCP↓,
Apoptosis↑,
cl‑Casp3↑,
cl‑PARP↑,
cl‑Casp9↑,
p‑PI3K↓, combination of baicalein and almonertinib can improve the antitumor activity in almonertinib-resistant NSCLC through the ROS-mediated PI3K/Akt pathway.
p‑Akt↓,
ROS↑, baicalein combined with almonertinib results in massive accumulation of reactive oxygen species (ROS)
eff↓, preincubation with N-acetyl-L-cysteine (ROS remover) prevents proliferation as well as inhibits apoptosis induction

1528- Ba,    Inhibiting reactive oxygen species-dependent autophagy enhanced baicalein-induced apoptosis in oral squamous cell carcinoma
- in-vitro, OS, CAL27
Apoptosis↑,
ROS↑, baicalein triggered reactive oxygen species (ROS) generation in Cal27 cells
eff↓, Furthermore, N-acetyl-cysteine, a ROS scavenger, abrogated the effects of baicalein on ROS-dependent autophagy.
TumAuto↑, baicalein increased autophagy through the promotion of ROS signaling pathways in OSCC.
cl‑PARP↑,
Bax:Bcl2↑,
Beclin-1↑, enhancement of Beclin-1 and degradation of p62
p62↓,

1529- Ba,    Studies on the Inhibitory Mechanisms of Baicalein in B16F10 Melanoma Cell Proliferation
- in-vitro, Melanoma, B16-F10
ROS↑,
eff↓, ROS scavengers effectively reversed cell viability reduction induced by baicalein
tumCV↓,
Casp3↑,
necrosis↑,

1531- Ba,    Proteomic analysis of the effects of baicalein on colorectal cancer cells
- in-vitro, CRC, DLD1 - in-vitro, CRC, SW48
TumCP↓,
ROS↓, reduced reactive oxygen species (ROS) by up-regulating the levels of peroxiredoxin-6 (PRDX6)
Prx6↑,
eff↓, Knockdown of PRDX6 in baicalein-treated CRC cells by specific small interfering RNA resulted in ROS production and proliferation
TumCCA↑, after baicalein treatment, the percentage of the S phase de- creased; those in the G1 phase rose to 45%, whereas those in the S and G2/M phase diminished to 22% and 33%.
ROS↝, Knocking down PRDX6 expression significantly promoted ROS product of the baicalein-treated DLD-1 cells
*ROS∅, baicalein up-regulates the expression of PRDX6, which attenuates the generation of ROS and inhibits the growth of CRC cells, whereas baicalein treatment have no effect on normal epithelial cells.

2047- BA,    Sodium butyrate inhibits migration and induces AMPK-mTOR pathway-dependent autophagy and ROS-mediated apoptosis via the miR-139-5p/Bmi-1 axis in human bladder cancer cells
- in-vitro, CRC, T24 - in-vitro, Nor, SV-HUC-1 - in-vitro, Bladder, 5637 - in-vivo, NA, NA
HDAC↓, Sodium butyrate (NaB) is a histone deacetylase inhibitor and exerts remarkable antitumor effects in various cancer cells
AntiTum↑,
TumCMig↓, NaB inhibited migration
AMPK↑, induced AMPK/mTOR pathway-activated autophagy and reactive oxygen species (ROS) overproduction via the miR-139-5p/Bmi-1 axis
mTOR↑,
TumAuto↑,
ROS↑, NaB initiates ROS overproduction
miR-139-5p↑, NaB upregulates miR-139-5p and depletes Bmi-1 in bladder cancer cells
BMI1↓,
TumCI?, NaB significantly inhibited cell migration dose-dependently
E-cadherin↑, E-cadherin was markedly increased, while the expression of N-cadherin, Vimentin, and Snail was decreased
N-cadherin↓,
Vim↓,
Snail↓,
cl‑PARP↑, increased expression levels of cleaved PARP, cleaved caspase-3, and Bax and the concurrent decrease in Bcl-2 and Bcl-xl
cl‑Casp3↑,
BAX↑,
Bcl-2↓,
Bcl-xL↓,
MMP↓, impairs mitochondrial membrane potential
PINK1↑, activates the PINK1/ PARKIN pathway
PARK2↑,
TumMeta↓, NaB inhibits tumor metastasis and growth in vivo
TumCG↓,
LC3II↑, a significant increase in the levels of cleaved caspase3, p-AMPK, and LC3B-II along with decreased Bmi-1 and Vimentin
p62↓, elevated LC3B-II levels and degradation of p62
eff↓, NAC abolished the impairment of MMP and ROS overproduction. Interestingly, NAC also significantly inhibited apoptosis induced by NaB

2290- Ba,    Research Progress of Scutellaria baicalensis in the Treatment of Gastrointestinal Cancer
- Review, GI, NA
p‑mTOR↓, Baicalein treatment decreased the expression levels of p-mTOR, p-Akt, p-IκB and NF-κB proteins, and suppressed GC cells by inhibiting the PI3K/Akt
p‑Akt↓,
p‑IKKα↓,
NF-kB↓,
PI3K↓,
Akt↓,
ROCK1↓, Baicalin reduces HCC proliferation and metastasis by inhibiting the ROCK1/GSK-3β/β-catenin signaling pathway
GSK‐3β↓,
CycB↓, Baicalein induces S-phase arrest in gallbladder cancer cells by down-regulating Cyclin B1 and Cyclin D1 in gallbladder cancer BGC-SD and SGC996 cells while up-regulating Cyclin A
cycD1↓,
cycA1↑,
CDK4↓, Following baicalein treatment, there is a down-regulation of Ezrin, CyclinD1, and CDK4, as well as an up-regulation of p53 and p21 protein levels, thereby leading to the induction of CRC HCT116 cell cycle arrest
P53↑,
P21↑,
TumCCA↑,
MMP2↓, baicalein was able to inhibit the metastasis of gallbladder cancer cells by down-regulating ZFX, MMP-2 and MMP-9.
MMP9↓,
EMT↓, Baicalein treatment effectively inhibits the snail-induced EMT process in CRC HT29 and DLD1 cells
Hif1a↓, Baicalein inhibits VEGF by downregulating HIF-1α, a crucial regulator of angiogenesis
Shh↓, baicalein inhibits the metastasis of PC by impeding the Shh pathway
PD-L1↓, Baicalin and baicalein down-regulate PD-L1 expression induced by IFN-γ by reducing STAT3 activity
STAT3↓,
IL1β↓, baicalein therapy significantly diminishes the levels of pro-inflammatory cytokines such as interleukin-1 beta (IL-1β), IL-2, IL-6, and GM-CSF
IL2↓,
IL6↓,
PKM2↓, Baicalein, by reducing the expression levels of HIF-1A and PKM2, can inhibit the glycolysis process in ESCC cells
HDAC10↓, Baicalein treatment increases the level of miR-3178 and decreases HDAC10 expression, resulting in the inactivation of the AKT signaling pathways.
P-gp↓, baicalein reverses P-glycoprotein (P-gp)-mediated resistance in multidrug-resistant HCC (Bel7402/5-FU) cells by reducing the levels of P-gp and Bcl-xl
Bcl-xL↓,
eff↓, Baicalein combined with gemcitabine/docetaxel promotes apoptosis of PC cells by activating the caspase-3/PARP signaling pathway
BioAv↓, baicalein suffers from low water solubility and susceptibility to degradation by the digestive system
BioAv↑, Encapsulation of baicalein into liposomal bilayers exhibits a therapeutic efficacy close to 90% for PDAC

2476- Ba,    Baicalein Induces Caspase-dependent Apoptosis Associated with the Generation of ROS and the Activation of AMPK in Human Lung Carcinoma A549 Cells
- in-vitro, Lung, A549
TumCG↓, baicalein-induced growth inhibition was associated with the induction of apoptosis in human lung carcinoma A549 cells.
Apoptosis↑,
DR5↑, Baicalein stimulated the expression of DR5, FasL, and FADD, and activated caspase-8 by reducing the levels of FLIPs (FLICE-inhibitory proteins).
FasL↑,
FADD↑,
Casp8↑,
cFLIP↓,
Casp9↑, activation of caspase-9 and -3, and cleavage of poly(ADP-ribose) polymerase
Casp3↑,
cl‑PARP↑,
MMP↓, Additionally, baicalein caused a mitochondrial membrane potential (MMP), the truncation of Bid, and the translocation of pro-apoptotic Bax to the mitochondria, thereby inducing the release of cytochrome c into the cytosol.
BID↑,
BAX↑,
Cyt‑c↑,
ROS↑, In turn, baicalein increased the generation of reactive oxygen species (ROS)
eff↓, however, an ROS scavenger, N-acetylcysteine, notably attenuated baicalein-mediated loss of MMP and activation of caspases.
AMPK↑, connected with ROS generation and AMPK activation.

1402- BBR,    Berberine-induced apoptosis in human glioblastoma T98G cells is mediated by endoplasmic reticulum stress accompanying reactive oxygen species and mitochondrial dysfunction
- in-vitro, GBM, T98G
tumCV↓,
ROS↑,
Ca+2↑,
ER Stress↑,
eff↓, administration of the antioxidants, N-acetylcysteine and glutathione, reversed berberine-induced apoptosis
Bax:Bcl2↑,
MMP↓,
Casp9↑,
Casp3↑,
cl‑PARP↑,

1404- BBR,    Berberine-induced apoptosis in human prostate cancer cells is initiated by reactive oxygen species generation
- in-vitro, Pca, PC3
Apoptosis↑,
*Apoptosis∅, not seen in non-neoplastic human prostate epithelial cells (PWR-1E)
MMP↓,
cl‑Casp3↑,
cl‑Casp9↑,
cl‑PARP↑,
ROS↑,
eff↓, Treatment of cells with allopurinol, an inhibitor of xanthine oxidase, inhibited berberine-induced oxidative stress in cancer cells.
Cyt‑c↑, release of cytochrome c

1385- BBR,  5-FU,    Low-Dose Berberine Attenuates the Anti-Breast Cancer Activity of Chemotherapeutic Agents via Induction of Autophagy and Antioxidation
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
eff↓, Berberine Attenuates the Anti-Breast Cancer Activity of Chemotherapeutic Agents
ROS↑, LDB mildly while HDB greatly stimulated ROS generation BBR-induced ROS generation may activate the antioxidant response therefore to promote cancer cell proliferation.
TumCP↑,
NRF2↑,
ChemoSen↓, These findings revealed a potential negative impact of BBR on its adjuvant anti-breast cancer therapy

1379- BBR,    Berberine derivative DCZ0358 induce oxidative damage by ROS-mediated JNK signaling in DLBCL cells
- in-vitro, lymphoma, NA
TumCP↓,
CDK4↓,
CDK6↓,
cycD1↓,
TumCCA↑, G0/G1 phase
MMP↓,
Ca+2↑,
ATP↓, decreased intracellular adenosine triphosphate production,
mtDam↑, mitochondrial dysfunction
Apoptosis↑,
ROS↑,
JNK↑,
eff↓, treatment with ROS scavenger N-acetylcysteine (NAC) and JNK inhibitor SP600125 could partially attenuate apoptosis and DNA damage triggered by DCZ0358.

1378- BBR,    Berberine induces non-small cell lung cancer apoptosis via the activation of the ROS/ASK1/JNK pathway
- in-vitro, Lung, NA
Apoptosis↑,
Casp3↑,
Cyt‑c↑, cytochrome c release
MMP↓,
p‑JNK↑,
eff↓, N-acetyl cysteine (NAC), a ROS scavenger, was sufficient to both suppress apoptosis signal-regulating kinase 1 (ASK1) and JNK activation and disrupt apoptotic induction.

2753- BetA,    Betulinic acid induces apoptosis by regulating PI3K/Akt signaling and mitochondrial pathways in human cervical cancer cells
- in-vitro, Cerv, HeLa
PI3K↓, BA treatment acted through downregulating a phosphatidylinositol 3-kinase (PI3K) subunit and suppressing the Akt phosphorylation at Thr308 and Ser473 after increasing the generation of intracellular reactive oxygen species
p‑Akt↓,
ROS↑,
TumCCA↑, BA induced cell cycle arrest at the G0/G1 phase, which was consistent with the cell cycle-related protein results in which BA significantly enhanced the expression of p27Kip and p21Waf1/Cip1 in HeLa cells.
p27↑,
P21↑,
mt-Apoptosis↑, mitochondrial apoptosis, as reflected by the increased expression of Bad and caspase-9
BAD↑,
Casp9↑,
MMP↓, decline in mitochondrial membrane potential.
eff↓, preincubation of the cells with glutathione (antioxidant) blocked the process of apoptosis, prevented the phosphorylation of downstream substrates.

2717- BetA,    Betulinic Acid Induces ROS-Dependent Apoptosis and S-Phase Arrest by Inhibiting the NF-κB Pathway in Human Multiple Myeloma
- in-vitro, Melanoma, U266 - in-vivo, Melanoma, NA - in-vitro, Melanoma, RPMI-8226
Apoptosis↑, BA mediated cytotoxicity in MM cells through apoptosis, S-phase arrest, mitochondrial membrane potential (MMP) collapse, and overwhelming reactive oxygen species (ROS) accumulation.
TumCCA↑, S-Phase Arrest in U266 Cells
MMP↓,
ROS↑, exhibited concentration-dependent increases in intracellular ROS
eff↓, ROS scavenger N-acetyl cysteine (NAC) effectively abated elevated ROS, the BA-induced apoptosis was partially reversed
NF-kB↓, BA resulted in marked inhibition of the aberrantly activated NF-κB pathway in MM
Cyt‑c↑, BA mediated the release of cyt c and activated cleaved caspase-3, caspase-8, and caspase-9 and cleaved PARP1
Casp3↑,
Casp8↑,
Casp9↑,
cl‑PARP1↑,
MDA↑, here is a concentration-dependent increase in MDA contents and reduction in SOD activities, especially for the high concentration group.
SOD↓,
SOD2↓, expression of genes SOD2, FHC, GCLM, and GSTM was all decreased following treatment with BA (40 μM)
GCLM↓,
GSTA1↓,
FTH1↓, FHC
GSTs↓, GSTM
TumVol↓, BA Inhibits the Growth of MM Xenograft Tumors In Vivo. BA-treated group were significantly reduced (inhibition ratio of approximately 72.1%).

2718- BetA,    The anti-cancer effect of betulinic acid in u937 human leukemia cells is mediated through ROS-dependent cell cycle arrest and apoptosis
- in-vitro, AML, U937
TumCCA↑, BA exerted a significant cytotoxic effect on U937 cells through blocking cell cycle arrest at the G2/M phase and inducing apoptosis, and that the intracellular reactive oxygen species (ROS) levels increased after treatment with BA.
Apoptosis↑,
i-ROS↑,
cycA1↓, down-regulation of cyclin A and cyclin B1, and up-regulation of cyclin-dependent kinase inhibitor p21WAF1/CIP1 revealed the G2/M phase arrest mechanism of BA.
CycB↓,
P21↑,
Cyt‑c↑, BA induced the cytosolic release of cytochrome c by reducing the mitochondrial membrane potential with an increasing Bax/Bcl-2 expression ratio.
MMP↓,
Bax:Bcl2↑,
Casp9↑, BA also increased the activity of caspase-9 and -3, and subsequent degradation of the poly (ADP-ribose) polymerase.
Casp3↑,
PARP↓,
eff↓, However, quenching of ROS by N-acetyl-cysteine, an ROS scavenger, markedly abolished BA-induced G2/M arrest and apoptosis, indicating that the generation of ROS plays a key role in inhibiting the proliferation of U937 cells by BA treatment.
*antiOx↑, Accumulated evidence demonstrates that BA possesses various biological activities, including antioxidant, anti-inflammatory, hepatoprotective, and anti-tumor effects
*Inflam↓,
*hepatoP↑,
selectivity↑, BA are complex and depends on the type of cancer cells, without causing toxicity toward normal cells
NF-kB↓, Shen et al. (2019) recently reported that the suppression of the nuclear factor-kappa B pathway increased downstream oxidant effectors, thereby promoting the generation of reactive oxygen species (ROS) in BA-stimulated multiple myeloma cells.
*ROS↓, Although BA is known to have antioxidant activity that blocks the accumulation of ROS due to oxidative stress in normal cells (Cheng et al. 2019;

2733- BetA,    Betulinic Acid Inhibits Cell Proliferation in Human Oral Squamous Cell Carcinoma via Modulating ROS-Regulated p53 Signaling
- in-vitro, Oral, KB - in-vivo, NA, NA
TumCP↓, BA dose-dependently inhibited KB cell proliferation and decreased implanted tumor volume.
TumVol↓,
mt-Apoptosis↑, BA significantly promoted mitochondrial apoptosis, as reflected by an increase in TUNEL+ cells and the activities of caspases 3 and 9, an increase in Bax expression, and a decrease in Bcl-2 expression and the mitochondrial oxygen consumption rate.
Casp3↑,
Casp9↑,
BAX↑,
Bcl-2↑,
OCR↓, BA dose-dependently decreased the oxygen consumption rate, indicating that BA induced a significant mitochondrial dysfunction
TumCCA↑, BA significantly increased cell population in the G0/G1 phase and decreases the S phase cell number, indicating the occurrence of G0/G1 cell cycle arrest.
ROS↑, ROS generation was significantly increased by BA
eff↓, and antioxidant NAC treatment markedly inhibited the effect of BA on apoptosis, cell cycle arrest, and proliferation.
P53↑, BA dose-dependently increased p53 expression in KB cells and implanted tumors.
STAT3↓, Inhibition of STAT3 Signaling Is Involved in BA-Induced Suppression of Cell Proliferation
cycD1↑, We found that BA mainly increased the mRNA expression of cyclin D1 but had no significant effect on cyclin E, CDK2, CDK4, or CDK6 expression.

2730- BetA,    Betulinic acid induces autophagy-dependent apoptosis via Bmi-1/ROS/AMPK-mTOR-ULK1 axis in human bladder cancer cells
- in-vitro, Bladder, T24
tumCV↓, The present study showed that BA exposure significantly suppressed viability, proliferation, and migration of EJ and T24 human bladder cancer cells
TumCP↓,
TumCMig↓,
Casp↑, These effects reflected caspase 3-mediated apoptosis
TumAuto↑, BA-induced autophagy was evidenced by epifluorescence imaging of lentivirus-induced expression of mCherry-GFP-LC3B and increased expression of two autophagy-related proteins, LC3B-II and TEM.
LC3B-II↑,
p‑AMPK↑, Moreover, enhanced AMPK phosphorylation and decreased mTOR and ULK-1 phosphorylation suggested BA activates autophagy via the AMPK/mTOR/ULK1 pathway.
mTOR↓,
BMI1↓, decreased Bmi-1 expression in BA-treated T24 cell xenografts in nude mice suggested that downregulation of Bmi-1 is the underlying mechanism in BA-mediated, autophagy-dependent apoptosis.
ROS↑, BA induced ROS production dose-dependently
eff↓, Co-incubation with NAC effectively blocked ROS production (Figure 4B), rescued cell viability,

2728- BetA,    Betulinic acid as new activator of NF-kappaB: molecular mechanisms and implications for cancer therapy
- in-vitro, Var, NA
NF-kB↑, BetA activates NF-kappaB in a variety of tumor cell lines.
IKKα↑, BetA-induced NF-kappaB activation involved increased IKK activity
eff↓, NF-kappaB inhibitors in combination with BetA would have no therapeutic benefit or could even be contraproductive in certain tumors, which has important implications for the design of BetA-based combination protocols.

3508- Bor,    The Effect of Boron on the UPR in Prostate Cancer Cells is Biphasic
- in-vitro, Pca, LNCaP - in-vitro, Pca, DU145
ER Stress↑, Treatment with 250 uM B induced endoplasmic reticulum (ER) stress in androgen dependent LNCaP and androgen independent DU-145 prostate cancer cell lines.
GRP78/BiP↑, this treatment induced BiP/GRP78, calreticulin and phosphorylation of eif2α the hallmarks of the unfolded protein response (UPR).
p‑eIF2α↑,
UPR↑,
eff↓, In contrast, concentrations of 1 uM B and 10 uM B rescued DU-145 cells respectively treated with 120 uM tunicamycin or 10 uM thapsigargin to induce ER stress.

744- Bor,    Borax affects cellular viability by inducing ER stress in hepatocellular carcinoma cells by targeting SLC12A5
- in-vitro, HCC, HepG2 - in-vitro, Nor, HL7702
TumCCA↑, cell cycle arrest in the G1/G0 phase
SLC12A5↓,
ATF6↑,
CHOP↑,
GRP78/BiP↑,
Casp3↑,
ER Stress↝,
*toxicity↓, HL‐7702 cells(normal) treated with 22.6 and 45.7 mM borax for 24 h showed no notable abnormalities in cellular size and cytoplasmic volume compared to the control group
*eff↓, tumour blood vessels absorb much higher levels of boric acid than normal liver tissues

1651- CA,  PBG,    Caffeic acid and its derivatives as potential modulators of oncogenic molecular pathways: New hope in the fight against cancer
- Review, Var, NA
Apoptosis↑,
TumCCA↓, CAPE (1-80 uM) can stimulate apoptosis and cell cycle arrest (G1 phase
TumCMig↓,
TumMeta↓,
ChemoSen↑,
eff↑, Nanoparticles promote therapeutic effect of CA and CAPE in reducing cancer cell malignancy.
eff↑, improve capacity of CA and CAPE in cancer suppression, it has been co-administered with other anti-tumor compounds such as gallic acid
eff↓, Currently, solvent extraction is utilized by methanol and ethyl acetate combination at high temperatures. However, a low amount of CA is yielded via this pathway
eff↝, Decyl CA (DCA) is a novel derivative of CA but its role in affecting colorectal cancer has not been completely understood.
Dose∅, The CAPE administration (0-60 uM) induces both autophagy and apoptosis in C6 glioma cells.
AMPK↑, CAPE induces autophagy via AMPK upregulation.
p62↓, CAPE can induce autophagy via p62 down-regulation and LC3-II upregulation
LC3II↑,
Ca+2↑, CA (0-1000 uM) enhances Ca2+ accumulation in cells in a concentration-dependent manner
Bax:Bcl2↑, CA can promote Bax/Bcl-2 ratio i
CDK4↑, The administration of CAPE (1–80 μM) can stimulate apoptosis and cell cycle arrest (G1 phase) via upregulation of Bax, CDK4, CDK6 and Rb
CDK6↑,
RB1↑,
EMT↓, CAPE has demonstrated high potential in inhibiting EMT in nasopharyngeal caner via enhancing E-cadherin levels, and reducing vimentin and β-catenin levels.
E-cadherin↑,
Vim↓,
β-catenin/ZEB1↓,
NF-kB↓,
angioG↑, CAPE (0.01-1ug/ml) inhibited angiogenesis via VEGF down-regulation
VEGF↓,
TSP-1↑, and furthermore, CAPE is capable of increasing TSP-1 levels
MMP9↓, CAPE was found to reduce MMP-9 expression
MMP2↓, CAPE can also down-regulate MMP-2
ChemoSen↑, role of CA and its derivatives in enhancing therapy sensitivity of cancer cells.
eff↑, CA administration (100 uM) alone or its combination with metformin (10 mM) can induce AMPK signaling
ROS↑, CA can promote ROS levels to induce cell death in human squamous cell carcinoma
CSCs↓, CA can reduce self-renewal capacity of CSCs and their migratory ability in vitro and in vivo.
Fas↑, CAPE (0-100 uM) is capable of inducing Fas signaling to promote p53 expression, leading to apoptotic cell death via Bax and caspase activation
P53↑,
BAX↑,
Casp↑,
β-catenin/ZEB1↓, anti-tumor activity of CAPE is mediated via reducing β-catenin levels
NDRG1↑, CAPE (30 uM) can promote NDRG1 expression via MAPK activation and down-regulation of STAT3
STAT3↓,
MAPK↑, CAPE stimulates mitogen-activated protein kinase (MAPK) and ERK
ERK↑,
eff↑, Res, thymoquinone and CAPE mediate lung tumor cell death via Bax upregulation and Bcl-2 down-regulation.
eff↑, co-administration of CA (100 μM) and metformin (10 mM) is of interest in cervical squamous cell carcinoma therapy.
eff↑, in addition to CA, propolis contains other agents such as chrysin, p-coumaric acid and ferulic acid that are beneficial in tumor suppression.

1653- Caff,    Higher Caffeinated Coffee Intake Is Associated with Reduced Malignant Melanoma Risk: A Meta-Analysis Study
- Review, Melanoma, NA
AntiCan↑, For caffeinated coffee, the pooled relative risk (RR) of MM was 0.81
eff↓, Strikingly, no significant association was found between the decaffeinated coffee intake level and MM risk

2015- CAP,  CUR,  urea,    Anti-cancer Activity of Sustained Release Capsaicin Formulations
- Review, Var, NA
AntiCan↑, Several convergent studies show that capsaicin displays robust cancer activity, suppressing the growth, angiogenesis and metastasis of several human cancers.
TumCG↓,
angioG↓,
TumMeta↓,
BioAv↓, clinical applications of capsaicin as a viable anti-cancer drug have remained problematic due to its poor bioavailability and aqueous solubility properties
BioAv↓, capsaicin is associated with adverse side effects like gastrointestinal cramps, stomach pain, nausea and diarrhea and vomiting
BioAv↑, All these hurdles may be circumvented by encapsulation of capsaicin in sustained release drug delivery systems.
selectivity↑, Most importantly, these long-acting capsaicin formulations selectively kill cancer cells and have minimal growth-suppressive activity on normal cells.
EPR↑, The EPR effect is a mechanism by which high–molecular drug delivery systems (typically prodrugs, liposomes, nanoparticles, and macromolecular drugs) tend to accumulate in tumor tissue much more than they do in normal tissues
eff↓, The efficiency of such extravasation is maximum when the size of the liposomes less than 200 nm The CAP-CUR-GLY-GAL-LIPO were spherical in shape with a narrow range of size distribution ranging from 135–155nm
ChemoSen↑, The chemosensitization and anti-tumor activity of capsaicin involves multiple molecular pathways
Dose∅, oral, Intravenous (IV), and Intraperitoneal (IP) options
Half-Life∅, oral metabolized in 105mins, T1/2in blood=25mins.
eff↑, presence of urea (as a carrier) increased the aqueous solubility of capsaicin by 3.6-fold compared to pure capsaicin

2019- CAP,    Capsaicin: A Two-Decade Systematic Review of Global Research Output and Recent Advances Against Human Cancer
- Review, Var, NA
chemoP↑, Capsaicin has shown significant prospects as an effective chemopreventive agent
Ca+2↑, Capsaicin was shown to cause upstream activation of Ca2+
antiOx↑, Another plausible mechanism implicated in the chemopreventive action of capsaicin is its anti-oxidative effects.
*ROS↓, capsaicin inhibits ROS release and the subsequent mitochondrial membrane potential collapse, cytochrome c expression, chromosome condensation, and caspase-3 activation induced by oxidized low-density lipoprotein in normal human HUVEC cells
*MMP∅,
*Cyt‑c∅,
*Casp3∅,
*eff↑, dietary curcumin and capsaicin concurrent administration in high-fat diet-fed rats were shown to mitigate the testicular and hepatic antioxidant status by increasing GSH levels, glutathione transferase activity, and Cu-ZnSOD expression
*Inflam↓, Anti-inflammation is another mechanism implicated in the chemopreventive action of capsaicin.
*NF-kB↓, inhibition of NF-kB by capsaicin
*COX2↓, compound elicits COX-2 enzyme activity inhibition and downregulation of iNOS
iNOS↓,
TRPV1↑, major pro-apoptotic mechanisms of capsaicin is via the vanilloid receptors, primarily TRPV1
i-Ca+2?, causing a concomitant influx of Ca2+: severe condition of mitochondria calcium overload. at high concentration (> 10 µM), capsaicin induces a slow but persistent increase in intracellular Ca2+
MMP↓, depolarization of mitochondria membrane potential
Cyt‑c↑, release of cytochrome C
Bax:Bcl2↑, activation of Bax and p53 through C-jun N-terminal kinase (JNK) activation
P53↑,
JNK↑,
PI3K↓, blocking the Pi3/Akt/mTOR signalling pathway, capsaicin increases levels of autophagic markers (LC3-II and Atg5)
Akt↓,
mTOR↓,
LC3II↑,
ATG5↑,
p62↑, enhances p62 and Fap-1 degradation and increases caspase-3 activity to induce apoptosis in human nasopharyngeal carcinoma cells
Fap1↓,
Casp3↑,
Apoptosis↑,
ROS↑, generation of ROS in human hepatoma (HepG2 cells)
MMP9↓, inhibition of MMP9 by capsaicin occurs via the suppression of AMPK-NF-κB, EGFR-mediated FAK/Akt, PKC/Raf/ERK, p38 MAPK, and AP-1 signaling pathway
eff↑, capsaicin 8% patch could promote the regeneration and restoration of skin nerve fibres in chemotherapy-induced peripheral neuropathy in addition to pain relief
eff↓, capsaicin has shown several unpleasant side effects, including stomach cramps, skin and gastric irritation, and burning sensation
eff↑, liposomes and micro-emulsion-based drugs have been known to significantly improve oral bioavailability and reduce the irritation of drugs
selectivity↑, In addition, these delivery systems can be surfaced-modified to perform site-directed/cell-specific drug delivery, thereby ensuring increased cell death of cancer cells while sparing non-selective normal cells
eff↑, Furthermore, owing to its antioxidant potential, capsaicin has been applied as a bioreduction and capping agent to synthesize biocompatible silver nanoparticles
ChemoSen↑, capsaicin has been combined with other anticancer therapies for more pronounced anticancer effects

1576- Citrate,    Targeting citrate as a novel therapeutic strategy in cancer treatment
- Review, Var, NA
TCA↓, Citrate serves as a key metabolite in the tricarboxylic acid cycle (TCA cycle, also referred to as the Krebs cycle)
T-Cell↝, modulation of T cell differentiation
Glycolysis↓, Citrate directly suppresses both cell glycolysis and TCA.
PKM2↓, citrate also inhibits glycolysis via its indirect inhibition of PK
PFK2?, In addition, citrate can inhibit PFK2,
SDH↓, citrate can inhibit enzymes, such as succinate dehydrogenase (SDH) and pyruvate dehydrogenase (PDH), in the TCA cycle
PDH↓,
β-oxidation↓, Citrate also inhibits β-oxidation as it promotes the formation of malonyl-CoA, which decreases the mitochondrial transport of fatty acids by inhibiting carnitine palmitoyl transferase I (CPT I)
CPT1A↓,
FASN↑, citrate has a positive role in promoting fatty acid synthesis
Casp3↑,
Casp2↑,
Casp8↑,
Casp9↑,
cl‑PARP↑,
Hif1a↓, Notably, in AML cell line U937, citrate induces apoptosis in a dose- and time-dependent manner by regulating the expression of HIF-1α and its downstream target GLUT-1
GLUT1↓,
angioG↓, citrate can also inhibit angiogenesis
Ca+2↓, chelate calcium ions in tumor cells
ROS↓, The other potential mechanism involved in citrate-mediated promotion of cancer growth and proliferation may be through its ability to decrease the levels of reactive oxygen species (ROS) in tumor cells
eff↓, dual effects of citrate in tumors may depend on the concentrations of citrate treatment, and different concentrations may bring out completely opposite effects even in the same tumor.
Dose↓, citrate concentration (<5 mM) appears to boost tumor growth and expansion in lung cancer A549 cells. 10mM and higher inhibited cell growth.
eff↑, citrate combined with ultraviolet (UV) radiation caused activation of caspase-3 and -9 in tumor cells (
Mcl-1↓, citrate has also been found to downregulate Mcl-1
HK2↓, Citrate also inhibits the enzymes PFK1 and hexokinase II (HK II) in glycolysis in tumor cells
IGF-1R↓,
PTEN↑, citrate may exert its effect via activating PTEN pathway
citrate↓, In addition to prostate cancer, citrate levels are significantly decreased in blood of patients with lung, bladder, pancreas and esophagus cancers
Dose∅, daily oral administration of citrate for 7 weeks at dose of 4 g/kg/day reduces tumor growth of several xenograft tumors and increases significantly the numbers of tumor-infiltrating T cells with no significant side effects in mouse models
eff↑, combining citrate with other compounds such as celecoxib, cisplatin, and 3-bromo-pyruvate, and have generated promising results
eff↑, combination of low effective doses of 3-bromo-pyruvate (3BP) (15uM), an inhibitor of glycolysis, and citrate (3 mM) significantly depleted the proliferation capability and migratory power of the C6 glioma
eff↑, Zinc treatment could lead to citrate accumulation in malignant prostate cells, which could have therapeutic potential in clinical therapy of prostate cancer.
eff↑, synergistic efficacy mediated by citrate combined with current checkpoint blockade therapies with anti-CTLA4 and/or anti-PD1/PDL1 will develop alternative novel strategies for future immunotherapy.

1577- Citrate,    Citric acid promotes SPARC release in pancreatic cancer cells and inhibits the progression of pancreatic tumors in mice on a high-fat diet
- in-vivo, PC, NA - in-vitro, PC, PANC1 - in-vitro, PC, PATU-8988 - in-vitro, PC, MIA PaCa-2
Apoptosis↑, citrate treatment demonstrates signifcant effcacy in promoting tumor cell apoptosis, suppressing cell proliferation, and inhibiting tumor growth in vivo
TumCP↓,
TumCG↑,
SPARC↑, citrate treatment reveal decreased glycolysis and oxygen consumption in tumor cells, increased SPARC protein expression, and the promotion of M1 polarization
Glycolysis↓,
OCR↓,
pol-M1↑, repolarizing M2 macrophages into M1 macrophages
pol-M2 MC↓, shift from the M2 phenotype to the M1 phenotype in TAMs following citrate treatment
Weight∅, no signficant changes in body weight observed between the two groups
ATP↓, decreased ATP production of pancreatic tumors in vivo
ECAR↓, signifcantly reduced glycolytic flux, glycolytic reserve, glycolytic capacity, and acidifcation rates
mitResp↓, decreased basal mitochondrial respiration
i-ATP↑, decrease in intracellular ATP levels
p65↓, citrate effectively suppressed the expression of RELA findings collectively underscore the critical role of RELA in mediating citrate's regulation of glycolysis and suppression of pancreatic cancer progression
i-Ca+2↑, inhibition of RELA resulted in a rapid elevation of intracellular calcium levels
eff↓, overexpression of RELA and SPARC knockdown attenuated the therapeutic effects of citrate

1585- Citrate,    Sodium citrate targeting Ca2+/CAMKK2 pathway exhibits anti-tumor activity through inducing apoptosis and ferroptosis in ovarian cancer
- in-vitro, Ovarian, SKOV3 - in-vitro, Ovarian, A2780S - in-vitro, Nor, HEK293
Apoptosis↑,
Ferroptosis↑,
Ca+2↓, Sodium citrate chelates intracellular Ca2+
CaMKII ↓, inhibits the CAMKK2/AKT/mTOR/HIF1α-dependent glycolysis pathway, thereby inducing cell apoptosis.
Akt↓,
mTOR↓,
Hif1a↓,
ROS↑, Inactivation of CAMKK2/AMPK pathway reduces Ca2+ level in the mitochondria by inhibiting the activity of the MCU, resulting in excessive ROS production.
ChemoSen↑, Sodium citrate increases the sensitivity of ovarian cancer cells to chemo-drugs
Casp3↑,
Casp9↑,
BAX↑,
Bcl-2↓,
Cyt‑c↑, co-localization of cytochrome c and Apaf-1
GlucoseCon↓, glucose consumption, lactate production and pyruvate content were significantly reduced
lactateProd↓,
Pyruv↓,
GLUT1↓, sodium citrate decreased both mRNA and protein expression levels of glycolysis-related proteins such as Glut1, HK2 and PFKP
HK2↓,
PFKP↓,
Glycolysis↓, sodium citrate inhibited glycolysis of SKOV3 and A2780 cells
Hif1a↓, HIF1α expression was decreased significantly after sodium citrate treatment
p‑Akt↓, phosphorylation of AKT and mTOR was notably suppressed after sodium citrate treatment.
p‑mTOR↓,
Iron↑, ovarian cancer cells treated with sodium citrate exhibited higher Fe2+ levels, LPO levels, MDA levels, ROS and mitochondrial H2O2 levels
lipid-P↑,
MDA↑,
ROS↑,
H2O2↑,
mtDam↑, shrunken mitochondria, an increase in mitochondrial membrane density and disruption of mitochondrial cristae
GSH↓, (GSH) levels, GPX activity and expression levels of GPX4 were significantly reduced in SKOV3 and A2780 cells with sodium citrate treatment
GPx↓,
GPx4↓,
NADPH/NADP+↓, significant elevation in the NADP+/NADPH ratio was observed with sodium citrate treatment
eff↓, Fer-1, NAC and NADPH significantly restored the cell viability inhibited by sodium citrate
FTH1↓, decreased expression of FTH1
LC3‑Ⅱ/LC3‑Ⅰ↑, sodium citrate increased the conversion of cytosolic LC3 (LC3-I) to the lipidated form of LC3 (LC3-II)
NCOA4↑, higher levels of NCOA4
eff↓, test whether Ca2+ supplementation could rescue sodium citrate-induced ferroptosis. The results showed that Ca2+ dramatically reversed the enhanced levels of MDA, LPO and ROS triggered by sodium citrate
TumCG↓, sodium citrate inhibited tumor growth by chelation of Ca2+ in vivo

1595- Cu,    The Multifaceted Roles of Copper in Cancer: A Trace Metal Element with Dysregulated Metabolism, but Also a Target or a Bullet for Therapy
- Review, NA, NA
eff↑, CuNPs can be used in a variety of therapeutic strategies, such as photothermal therapy combined with immunotherapies, to induce systemic immune responses against tumors
ROS↑, One of the approaches aims at producing excess ROS by exploiting the properties of certain metals, which will lead to the death of cancer cells
eff↓, cancer tumor have higher copper, and feeding them copper may accelerate growth.

1596- Cu,  CDT,    Unveiling the promising anticancer effect of copper-based compounds: a comprehensive review
- Review, NA, NA
TumCD↑, Copper and its compounds are capable of inducing tumor cell death through various mechanisms of action, including activation of apoptosis signaling pathways by reactive oxygen species (ROS), inhibition of angiogenesis, induction of cuproptosis, and p
Apoptosis↓,
ROS↑,
angioG↑,
Cupro↑,
Paraptosis↑,
eff↑, copper nanoparticles can be used as effective agents in chemodynamic therapy, phototherapy, hyperthermia, and immunotherapy.
eff↓, Elevated copper concentrations may promote tumor growth, angiogenesis, and metastasis by affecting cellular processes
selectivity↑, Copper nanoparticles also can selectively attack cancer cells and spare healthy cells This selectivity is attributed to the EPR effect, which enables nanoparticles to accumulate in tumor tissue by exploiting leaky blood vessels
DNAdam↑, Copper has been found to induce DNA damage and oxidation through the formation of ROS.
eff↑, Tumor cells suffering from oxygen deficiency often have an increased concentration of CTR-1, which facilitates the transport of copper(I) into the cells
eff↑, The results demonstrate the promising capabilities of 64CuCl2 as a valuable tool for both diagnosis and therapy in various types of cancer
eff↑, nanoparticles have remarkable properties, including a large surface area to volume ratio, excellent compatibility with living organisms, and the ability to generate ROS when exposed to an acidic tumor microenvironment
eff↑, Several studies have shown that copper nanoparticles can be used as effective agents in chemodynamic therapy (CDT)
Fenton↑, CDT is a promising treatment strategy for cancer that utilizes the in situ Fenton reaction, which is activated by endogenous substances, such as GSH and H2O2 without the need for external energy input
H2O2↑, Copper-based substrates have been developed that generate H2O2 internally and function effectively in weakly acidic tumor microenvironments (TME)
eff↑, metal peroxide nanomaterials and offers a promising strategy to improve CDT efficacy
eff↑, Copper nanoparticles can also be used in phototherapy
eff↑, Copper nanoparticles have also shown success in destroying cancer tissue by hyperthermia. This method is a local anticancer treatment in which cells are exposed to high temperatures.
RadioS↑, promising results when used in combination with radiotherapy or chemotherapy for various tumor types.
ChemoSen↑,
eff↑, copper nanoparticles are promising in cancer immunotherapy because they enhance immune-based therapies
*toxicity↝, Copper is a necessary trace mineral for the human body, but high concentrations of copper can be toxic
other↑, Extensive research has shown that cancer cells require an increased copper content to support their rapid growth compared to normal cells
eff↑, Copper nanoparticles can be used to generate heat when exposed to certain wavelengths of light or alternating magnetic fields.

1598- Cu,    Targeting copper in cancer therapy: 'Copper That Cancer'
- Review, NA, NA
eff↓, copper serves as a limiting factor for multiple aspects of tumor progression, including growth, angiogenesis and metastasis, has prompted the development of copper-specific chelators as therapies to inhibit these processes.
eff↑, Another therapeutic approach utilizes specific ionophores that deliver copper to cells to increase intracellular copper levels.
Dose∅, therapeutic window between normal and cancerous cells when intracellular copper is forcibly increased, is the premise for the development of copper-ionophores endowed with anticancer properties.
eff↑, In comparison to platinum-based drugs, these promising copper coordination complexes may be more potent anticancer agents, with reduced toxicity toward normal cells and they may potentially circumvent the chemoresistance
angioG↑, These findings unquestionably place copper as a potent inducer of the angiogenic process.
ROS↑, Copper is a redox active metal that can enhance the production of ROS, which subsequently can damage most biomolecules

1604- Cu,    Targeting copper metabolism: a promising strategy for cancer treatment
- Review, NA, NA
eff↓, Cancer cells have been shown to have higher copper levels compared to normal cells. Thus, by reducing the amount of copper available to cancer cells, it is possible to sensitize them to chemotherapy and radiotherapy.
eff↓, copper depletion sensitized ovarian cancer cells to radiation therapy by increasing the production of reactive oxygen species and inducing DNA damage
ROS↑, When CuO NPs enter cancer cell, they can interact with intracellular copper ions and generate ROS, such as hydrogen peroxide (H2O2) and superoxide anion
eff↑, Copper (II) complexes of curcumin have been shown to have enhanced anti-cancer activity compared to curcumin alone due to their ability to induce cancer cell death via multiple mechanisms, including the generation of reactive oxygen species

1409- CUR,    Curcumin analog WZ26 induces ROS and cell death via inhibition of STAT3 in cholangiocarcinoma
- in-vivo, CCA, Walker256
TumCG↓,
ROS↑,
MMP↓,
STAT3↓,
TumCCA↑, G2/M cell cycle
eff↓, Pretreatment of N-acetyl cysteine (NAC), an antioxidant agent, could fully reverse the WZ26-induced ROS-mediated changes in CCA cells

2978- CUR,    N-acetyl cysteine mitigates curcumin-mediated telomerase inhibition through rescuing of Sp1 reduction in A549 cells
- in-vitro, Lung, A549
ROS↑, ROS induced by curcumin in A549 cells was detected by flow cytometry
hTERT↓, human telomerase reverse transcriptase (hTERT) decreased in the presence of curcumin
Sp1/3/4↓, curcumin decreases the expression of Sp1 through proteasome pathway
eff↓, NAC blunted the Sp1 reduction and hTERT downregulation by curcumin.

2812- CUR,    Curcumin Induces High Levels of Topoisomerase I− and II−DNA Complexes in K562 Leukemia Cells
- in-vitro, AML, K562
TOP1↑, this study shows for the first time that curcumin induces topo I and topo II (α and β)−DNA complexes in K562 leukemia cells.
TOP2↑,
eff↓, Curcumin-induced topo I and topo II−DNA complexes were prevented by the antioxidant N-acetylcysteine; this suggests that, unlike the standard topo inhibitors, reactive oxygen species may mediate the formation of these complexes

1887- DCA,    GSTZ1 expression and chloride concentrations modulate sensitivity of cancer cells to dichloroacetate
- in-vitro, Var, NA
GSTZ1∅, high levels of GSTZ1 expression confers resistance to the effect of high concentrations of DCA on cell viability
eff↓, These results may have important clinical implications in determining intratumoral metabolism of DCA and, consequently, appropriate oral dosing.
PDKs↓, inhibitor of mitochondrial pyruvate dehydrogenase kinase (PDK), DCA maintains the pyruvate dehydrogenase complex (PDC) in its active, unphosphorylated state
Chl∅, [Cl-] in tumors is often abnormally high compared to the surrounding tissue
eff↓, changes in [Cl-] could have an impact on DCA treatment, because a tumor with high GSTZ1 expression and high [Cl-] could exhibit atypical resistance to the anti-tumor effects of the drug.

1885- DCA,    Role of SLC5A8, a plasma membrane transporter and a tumor suppressor, in the antitumor activity of dichloroacetate
- in-vitro, CRC, HCT116 - in-vitro, CRC, SW-620 - in-vitro, CRC, HT-29
SMCT1∅, SLC5A8 transports dichloroacetate very effectively with high affinity. This transporter is expressed in normal cells, but the expression is silenced in tumor cells via epigenetic mechanisms.
eff↓, lack of the SLC5A8 transporter makes tumor cells resistant to the antitumor activity of dichloroacetate.
eff↑, However, if the transporter is expressed in tumor cells ectopically, the cells become sensitive to the drug at low concentrations. This is evident in breast cancer cells, colon cancer cells, and prostate cancer cells.
eff↑, our findings suggest that combining dichloroacetate with a DNA methylation inhibitor would offer a means to reduce the doses of dichloroacetate to avoid detrimental effects associated with high doses but without compromising antitumor activity.
PDKs↓, Dichloroacetate is an inhibitor of pyruvate dehydrogenase kinase (PDK), which phosphorylates the E1α subunit of PDC and inactivates the complex
MMP↓, depolarization of the mitochondrial membrane,
Glycolysis↓, suppression of glycolysis
mitResp↑, enhancement of mitochondrial oxidation
ROS↑, production of reactive oxygen species,
eff↑, In control cells, which did not express the transporter, dichloroacetate did not have any significant effect. However, under identical conditions, SLC5A8-expressing cells underwent apoptosis to a marked extent. This phenomenon was seen in all three c

1847- dietFMD,  VitC,    Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers
- in-vitro, PC, PANC1
TumCG↓, Fasting-mimicking diets delay tumor progression
ChemoSen↑, sensitize a wide range of tumors to chemotherapy
eff↑, vitamin C anticancer activity is limited by the up-regulation of the stress-inducible protein heme-oxygenase-1. The fasting-mimicking diet selectivity reverses vitamin C-induced up-regulation of heme-oxygenase-1
HO-1↓, FMD reverses the effect of vitamin C on HO-1(downregulating HO-1)
Ferritin↓,
Iron↑, consequently increasing reactive iron, oxygen species, and cell death
ROS↑, Vitamin C’s pro-oxidant action is strictly dependent on metal-ion redox chemistry. In particular, free iron was shown to be a key player in vitamin C-induced cytotoxic effects
TumCD↑,
IGF-1↓, effects on the insulin-like growth factor 1 (IGF-1)
eff↓, When cancer cells were grown under STS conditions before and during treatment, vitamin C-mediated toxicity was strongly enhanced
eff↓, Conversely, KRAS-wild-type CRC (SW48, HT29), prostate cancer (PC-3), ovarian cancer (COV362) cell lines and a normal colon cell line (CCD841CoN) were resistant to vitamin C when used both as a single agent and in combination with STS

2265- dietMet,    Cysteine supplementation reverses methionine restriction effects on rat adiposity: significance of stearoyl-coenzyme A desaturase
- in-vivo, Nor, NA
*SCD1↓, Dietary methionine restriction in rats decreases hepatic Scd1 mRNA and protein,
*Weight↓, MR markedly lowered weight gain, as previously reported (21, 22, 28), despite food intake/g body weight being consistently higher than CF group throughout the study
*Insulin↓, MR significantly decreased serum concentrations of insulin, leptin, IGF-1, and raised adiponectin compared with CF.
*IGF-1↓,
*adiP↑,
*eff↓, these effects were reversed by cysteine

2266- dietMet,    Cysteine dietary supplementation reverses the decrease in mitochondrial ROS production at complex I induced by methionine restriction
- in-vivo, Nor, NA
*ROS↓, decrease in mitochondrial ROS generation induced by methionine restriction at complex I
eff↓, results obtained in liver showed that cysteine supplementation reverses the decrease in mitochondrial ROS generation induced by methionine restriction

3708- dietSTF,    Fasting as a Therapy in Neurological Disease
*PGC-1α↑, figure 1
*AMPK↑,
*adiP↑,
*glucose↓,
*Insulin↓,
*mTOR↓,
*IL6↓,
*TNF-α↓,
*cognitive↑, or even enhanced—cognitive performance
*Inflam↓, fasting suppresses inflammation, reducing the expression of pro-inflammatory cytokines such as interleukin 6 (IL6) and tumor necrosis factor α (TNFα)
*eff↑, mice fasted on alternate days can eat twice as much on the feeding day, such that their net weekly calorie intake remains similar to mice fed ad libitum; despite the lack of overall calorie restriction, the former still display beneficial metabolic e
*neuroP↑, Fasting can also prevent and treat many neurological disorders in animals;
ChemoSen↑, fasting has been shown to improve the therapeutic responses of a variety of rodent cancer models, including gliomas, to chemotherapy
eff↓, shorter nightly fasts were associated with an increased recurrence of cancer
chemoP↑, fasting before or after chemotherapy decreased chemotherapy-related adverse effects, such as weakness, fatigue, and gastrointestinal upset
*eff↑, implementation of a fasting regimen after a traumatic brain injury confers neuroprotection and improves functional recovery

660- EGCG,  FA,    Epigallocatechin-3-gallate Delivered in Nanoparticles Increases Cytotoxicity in Three Breast Carcinoma Cell Lines
- in-vitro, BC, MDA-MB-231 - in-vitro, BC, MCF-7 - in-vitro, Nor, MCF10
Apoptosis↑, EGCG nanodelivery lower concentrations
*toxicity↓, We can confirm that EGCG do not harm normal cells, either delivered in LNPs or free
*eff↓, preferentially entered cancer cells whereas they were poorly assumed by normal cells

1516- EGCG,    Epigallocatechin Gallate (EGCG): Pharmacological Properties, Biological Activities and Therapeutic Potential
- Review, NA, NA
*Dose∅, A pharmacokinetic study in healthy individuals receiving single doses of EGCGrevealed that plasma concentrations exceeded 1 μM only with doses of >1 g
Half-Life∅, peak levels observed between 1.3 and 2.2 h (and a half-life (t1/2z) of 1.9 to 4.6 h)
BioAv∅, oral bioavailability of 20.3% relative to intravenous admistration
BBB↑, EGCG can cross the blood–brain barrier, allowing it to reach the brain
toxicity∅, Isbrucher et al. found no evidence of genotoxicity in rats following oral administration of EGCG at doses of 500, 1000, or 2000 mg/kg, or intravenous injections of 10, 25, or 50 mg/kg/day.
eff↓, interaction with the folate transporter has been reported, leading to reduced bioavailability of folic acid
Apoptosis↑,
Casp3↑,
Cyt‑c↑, cytochrome c release
cl‑PARP↑,
DNMTs↓,
Telomerase↓,
angioG↓,
Hif1a↓,
NF-kB↓,
MMPs↓,
BAX↑,
Bak↑,
Bcl-2↓,
Bcl-xL↓,
P53↑,
PTEN↑,
IGF-1↓,
H3↓,
HDAC1↓,
*LDH↓, reduces LDL cholesterol, decreases oxidative stress by neutralizing ROS
*ROS↓,

3220- EGCG,    Dual Roles of Nrf2 in Cancer
- in-vitro, Lung, A549
NRF2↑, Examples of potent Nrf2 inducers from plants include sulforaphane, curcumin, EGCG, resveratrol, caffeic acid phenethyl ester, wasabi, cafestol and kahweol (coffee), cinnamon, ginger, garlic, lycopene, rosemany
eff↓, A549 is more resistant to cisplatin and EGCG induced cell death than any other lung cancer cell line. This was contributed to the high expression of Nrf2 and HMOX-1

1329- EMD,    Aloe-emodin induces cell death through S-phase arrest and caspase-dependent pathways in human tongue squamous cancer SCC-4 cells
- in-vitro, Tong, SCC4
TumCCA↑, S-phase arrest
eff↓, The free radical scavenger N-acetylcysteine (NAC) and caspase inhibitors markedly blocked aloe-emodin-induced apoptosis
P53↑,
P21↑,
p27↑,
cycA1↓,
cycE↓,
TS↓,
CDC25↓, Cdc25A
AIF↑, promoted the release of apoptosis-inducing factor (AIF)
proCasp9↓,
Cyt‑c↑,
MMP↓,
Bax:Bcl2↑,
Casp3↑,
Casp9↑,

2204- erastin,    Regulation of ferroptotic cancer cell death by GPX4
- in-vitro, fibroS, HT1080
GSH↓, Erastin Depletes Glutathione to Trigger Selective Ferroptosis
Ferroptosis↑,
ROS↑, erastin induces the formation of ROS, causing an oxidative cell death.
GPx↓, GSH Depletion Inactivates GPX Enzymes to Induce Ferroptosis
GPx4↓, RSL3 Binds to and Inactivates GPX4
lipid-P↑, lipid oxidation is common to both erastin-induced and RSL3-induced ferroptotic cell death
eff↓, Although erastin displayed synthetic lethality in the engineered cells, it did not show selective lethality in RAS-mutated cancer cell lines over RAS wild-type counterparts
eff↑, DLBCLs were more sensitive to erastin than AML and MM cells.

2150- Ex,    Roles and molecular mechanisms of physical exercise in cancer prevention and treatment
- Review, Var, NA
eff↓, Physical exercise should be considered an important intervention to prevent and treat cancer and its complications.
Dose↝, Sensitivity to physical exercise varies in different cancers; we provide evidence for the exercise type and strength in various cancers and in differing stages.
TumCP↓, nhibiting cancer cell proliferation and inducing apoptosis and regulating metabolism and the immune environment are the main mechanisms of the benefits of physical exercise in cancer prevention and treatment.
Apoptosis↓,
ChemoSen↑, Graphic Abstract
chemoP↑, Graphic Abstract

1622- FA,    Folate and Its Impact on Cancer Risk
- Review, NA, NA
eff↓, Low or deficient folate status is associated with increased risk of many cancers

2498- Fenb,    Unexpected Antitumorigenic Effect of Fenbendazole when Combined with Supplementary Vitamins
- in-vivo, lymphoma, NA
eff↓, Neither diet supplemented with vitamins alone nor fenbendazole alone caused altered tumor growth as compared with that of controls.
eff↑, However, the group supplemented with both vitamins and fenbendazole exhibited significant inhibition of tumor growth
TumVol↓, Tumors in the fenbendazole plus vitamin group were significantly smaller (P = 0.009) and delayed in initial growth compared with those of the control group
antiOx↑, Supplemented vitamins included B, D, K, E, and A. Vitamins E and A both have antitumor properties by virtue of their antioxidant properties.
Hif1a↓, some antioxidants may exert their antitumor effects through reducing HIF

2847- FIS,    Fisetin-induced cell death, apoptosis, and antimigratory effects in cholangiocarcinoma cells
- in-vitro, CCA, NA
tumCV↓, Fisetin was significant in suppressing CCA cell viability and colony formation during the course of this experiment.
ChemoSen↑, fisetin significantly potentiated the cisplatin-induced CCA cells death
TumCMig↓, reduced the migration of cancer cells and demonstrated more pronounced effects on KKU-M452 cells
ROS↑, fisetin prompted cell death and apoptosis in CCA cells by stimulating the generation of ROS in KKU-100 cells at a dosage of 50 μM
TumCI↓, suppression of cell invasion and migration,prevention of angiogenesis
angioG↓,
CDK2↓, mechanisms including the suppression of cyclin-dependent kinases, the inhibition of PI3K/Akt/mTOR
PI3K↓,
Akt↓,
mTOR↓,
EGFR↓, suppression of the EGFR pathway, the stimulation of the caspase cascade
Casp↑,
mTORC1↓, suppressing the mTORC1 and 2 signaling
mTORC2↑,
cycD1↓, decreasing the level of the cyclin D1 and cyclin E mRNA
cycE↓,
MMP2↓, Matrix metalloproteinases (MMP) 2 and MMP 9 gene expression and enzyme activity are suppressed
MMP9↓,
ER Stress↑, Moreover, fisetin also caused endoplasmic reticulum (ER) stress-induced production of mitochondrial ROS generation and Ca2+, with the involvement of MAPK signaling
Ca+2↑,
eff↓, The ROS scavenger molecule N-acetyl cysteine decreased fisetin-activated apoptosis in multiple myeloma and oral cancer cells

2849- FIS,    Activation of reactive oxygen species/AMP activated protein kinase signaling mediates fisetin-induced apoptosis in multiple myeloma U266 cells
- in-vitro, Melanoma, U266
TumCD↑, Fisetin elicited the cytotoxicity in U266 cells, manifested as an increased fraction of the cells with sub-G1 content or stained positively with TUNEL labeling
TumCCA↑,
Casp3↑, Fisetin enhanced caspase-3 activation, downregulation of Bcl-2 and Mcl-1L, and upregulation of Bax, Bim and Bad
Bcl-2↓,
Mcl-1↓,
BAX↑,
BIM↑,
BAD↑,
AMPK↑, Fisetin activated AMPK as well as its substrate acetyl-CoA carboxylase (ACC), along with a decreased phosphorylation of AKT and mTOR.
ACC↑,
p‑Akt↓,
p‑mTOR↓,
ROS↑, Fisetin also stimulated generation of ROS in U266 cells
eff↓, Conversely, compound C or N-acetyl-l-cystein blocked fisetin-induced apoptosis

2842- FIS,    Fisetin inhibits cellular proliferation and induces mitochondria-dependent apoptosis in human gastric cancer cells
- in-vitro, GC, AGS
TumCCA↑, Fisetin (25-100 μM) caused significant decrease in the levels of G1 phase cyclins and CDKs, and increased the levels of p53 and its S15 phosphorylation in gastric cancer cells.
CDK2↓,
P53↑,
selectivity↑, observed that growth suppression and death of non-neoplastic human intestinal FHs74int cells were minimally affected by fisetin
MMP↓, Fisetin strongly increased apoptotic cells and showed mitochondrial membrane depolarization in gastric cancer cells
DNAdam↑, DNA damage was observed as early as 3 h after fisetin treatment which was accompanied with gamma-H2A.X(S139) phosphorylation and cleavage of PARP
cl‑PARP↑,
mt-ROS↑, showed an increase in mitochondrial ROS generation in time- and dose-dependent fashion
eff↓, Pre-treatment with N-acetyl cysteine (NAC) inhibited ROS generation and also caused protection from fisetin-induced DNA damage
survivin↓, We observed a decrease in the levels of survivin by fisetin in gastric cancer cells which further strengthens our results that fisetin decreases antiapoptotic proteins to promote apoptosis.

1971- GamB,    Gambogic acid triggers vacuolization-associated cell death in cancer cells via disruption of thiol proteostasis
- in-vitro, Nor, MCF10 - in-vitro, BC, MDA-MB-435 - in-vitro, BC, MDA-MB-468 - in-vivo, NA, NA
Paraptosis↑, GA kills cancer cells by inducing paraptosis, a vacuolization-associated cell death.
ER Stress↑, GA-induced proteasomal inhibition was found to contribute to the ER dilation and ER stress seen in treated cancer cells
MMP↓, mitochondrial membrane depolarization.
eff↓, GA-induced paraptosis was effectively blocked by various thiol-containing antioxidants
selectivity↑, MCF-10A (normal) cells were relatively resistant to this effect of GA at doses up to 3 μM
p‑ERK↑, In cells treated with 1 μM GA, the phosphorylation levels of ERKs and JNKs were markedly increased
p‑JNK↑,
eff↓, Interestingly, the general antioxidant, N-acetylcysteine (NAC), but not the mitochondria-targeted antioxidant, Tiron19, dose-dependently blocked GA-induced cell death and vacuolation in all of the tested cancer cell lines

1970- GamB,    Gambogic acid-induced autophagy in nonsmall cell lung cancer NCI-H441 cells through a reactive oxygen species pathway
- NA, Lung, NCI-H441
TumCG↓, NCI‑H441 is a human lung adenocarcinoma cell line that is widely used as a model system for studying pulmonary epithelial functions, particularly those of alveolar type II cells.
TumAuto↑, GA induced NCI-H441 cells autophagy
Beclin-1↑, upregulation of Beclin 1
LC3‑Ⅱ/LC3‑Ⅰ↑, conversion of LC3 I to LC3 II (autophagosome marker)
ROS↑, generated ROS
eff↓, ROS scavenger N-acetylcysteine reversed GA-induced autophagy and restored the cell survival, which indicated GA-induced autophagy in NCI-H441 cells through an ROS-dependent pathway.

1957- GamB,    Nanoscale Features of Gambogic Acid Induced ROS-Dependent Apoptosis in Esophageal Cancer Cells Imaged by Atomic Force Microscopy
- in-vitro, ESCC, EC9706
AntiCan↑, Gambogic acid (GA), a kind of polyprenylated xanthone derived from Garcinia hanburyi tree, has showed spectrum anticancer effects both in vitro and in vivo with low toxicity.
toxicity↓,
TumCP↓, GA could inhibit cell proliferation, induce apoptosis, induce cell cycle arrest,
Apoptosis↑,
TumCCA↑, GA could induce EC9706 cell cycle arrest at G2/M phase in ROS-dependent way
MMP↓, induce mitochondria membrane potential disruption in a ROS-dependent way.
ROS↑,
eff↓, removal of GA-induced excessive ROS by N-acetyl-L-cysteine (NAC) could reverse GA-inhibited EC9706 cell proliferation
RadioS↑, GA is also found to enhance the radiosensitivity of human esophageal cancer cells

1958- GamB,    Gambogenic acid induces apoptosis and autophagy through ROS-mediated endoplasmic reticulum stress via JNK pathway in prostate cancer cells
- in-vitro, Pca, NA - in-vivo, NA, NA
AntiCan↑, Gambogenic acid (GNA), a flavonoids compound isolated from Gamboge, exhibits anti-tumor capacity in various cancers.
TumCP↓, GNA revealed not only antiproliferative and pro-apoptotic activities but also the induction of autophagy in PCa cells.
TumAuto↑,
eff↑, In addition, autophagy inhibitor chloroquine enhanced the pro-apoptosis effect of GNA.
JNK↑, activation of JNK pathway
ROS↑, GNA significantly promoted reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress.
ER Stress↑,
eff↓, ROS scavenger N-acetyl-L-cysteine (NAC) effectively abrogated ER stress and JNK pathway activation induced by GNA.
TumCG↓, GNA remarkably suppressed prostate tumor growth with low toxicity in vivo.

1959- GamB,    Gambogic acid induces GSDME dependent pyroptotic signaling pathway via ROS/P53/Mitochondria/Caspase-3 in ovarian cancer cells
- in-vitro, Ovarian, NA - in-vivo, NA, NA
AntiCan↑, Gambogic acid (GA) is a naturally active compound extracted from the Garcinia hanburyi with various anticancer activities.
Pyro↑, This study revealed that GA treatment reduced cell viability by inducing pyroptosis in OC cell lines
tumCV?,
CellMemb↓, loss of cell membrane integrity
cl‑Casp3↑, Cleaved caspase-3 and GSDME-N levels increased after GA treatment
GSDME-N↑,
ROS?, GA significantly increased reactive oxygen species (ROS) and p53 phosphorylation.
p‑P53↑,
eff↓, OC cells pretreated with ROS inhibitor N-Acetylcysteine (NAC) and the specific p53 inhibitor pifithrin-μ could completely reverse the pyroptosis post-treatment.
MMP↓, Elevated p53 and phosphorylated p53 reduced mitochondrial membrane potential (MMP) and Bcl-2
Bcl-2↓,
BAX↑,
mtDam↑, damage mitochondria by releasing cytochrome c to activate the downstream pyroptosis pathway
Cyt‑c↑,
TumCG↓, inhibited tumor growth in ID8 tumor-bearing mice
CD4+↑, high-dose GA increased in tumor-infiltrating lymphocytes CD3, CD4, and CD8 were detected in tumor tissues
CD8+↑,

1961- GamB,    Effects of gambogic acid on the activation of caspase-3 and downregulation of SIRT1 in RPMI-8226 multiple myeloma cells via the accumulation of ROS
- in-vitro, Melanoma, RPMI-8226
TumCG↓, GA was found to have a significant, dose-dependent effect on growth inhibition and apoptosis induction in RPMI-8226 cells.
Apoptosis↑,
ROS↑, This activity is associated with the accumulation of ROS
Casp3↑, which contributes to the activation of caspase-3 and the cleavage of poly (ADP-ribose) polymerase (PARP)
cl‑PARP↑,
SIRT1↓, demonstrated that GA has the potential to downregulate the expression of SIRT1 via ROS accumulation.
eff↓, NAC reduced the apoptosis rate in RPMI-8226 cells treated with GA

823- GAR,    Garcinol Potentiates TRAIL-Induced Apoptosis through Modulation of Death Receptors and Antiapoptotic Proteins
- in-vitro, BC, MCF-7 - in-vitro, Nor, MCF10 - in-vitro, CRC, HCT116
Casp3↑,
Casp9↑,
Casp8↑,
DR5↑,
survivin↓,
Bcl-2↓,
XIAP↓,
cFLIP↓,
BAX↑,
Cyt‑c↑,
ROS↑, ROS in MCF-7 breast cancer cells, the production of ROS was not observed in non-tumorigenic MCF-10A
GSH↓, Glutathione (GSH) also abolished the garcinol-induced induction of both DR5 and DR4 expression in a dose-dependent manner
*eff↓, Garcinol neither induced the receptors on normal cells, nor sensitized them to TRAIL

2509- H2,    Hydrogen inhibits endometrial cancer growth via a ROS/NLRP3/caspase-1/GSDMD-mediated pyroptotic pathway
- in-vitro, Endo, AN3CA - in-vivo, Endo, NA
selectivity↑, Hydrogen exerts a biphasic effect on cancer by promoting tumor cell death and protecting normal cells, which might initiate GSDMD pathway-mediated pyroptosis.
mt-ROS↑, We therefore concluded that molecular hydrogen activated ROS and mtROS generation in endometrial cancer cells.
ROS↑,
TumW↓,
GSDMD↑, ability of hydrogen to stimulate NLRP3 inflammasome/GSDMD activation in pyroptosis
Pyro↑,
Dose↝, Hydrogenated water was produced by H2 dissolved in water saturantly under 0.4 MPa pressure for 6 h with a concentration of 1.0 ppm produced by hydrogen water apparatus
eff↓, In contrast, NAC decreased ROS levels in hydrogen-treated endometrial cancer cells
TumVol↓, We demonstrated that drinking hydrogen-rich water reduced the volume of endometrial tumors in a xenograft mouse model.

1629- HCA,  Tam,    Hydroxycitric acid reverses tamoxifen resistance through inhibition of ATP citrate lyase
- in-vitro, BC, MCF-7
ACLY↓, Hydroxycitric acid (HCA) is a powerful competitive inhibitor of the enzyme ACLY
eff↓, co-treatment synergistically diminished LCC2 and MCF7 cell viability
tumCV↓,
eff↑, co-treatment decreases the expression level of ACLY in LCC2 by 74 %, while in MCF7 by only 59 %
Casp3↑,
BAX↑,
Bcl-2↓,

1439- HCQ,    Acidic extracellular pH neutralizes the autophagy-inhibiting activity of chloroquine
- in-vitro, Melanoma, NA - in-vitro, CRC, HCT116
TumAuto↓, Inhibition of autophagy by administration of chloroquine (CQ) in combination anticancer therapies is currently evaluated in clinical trials.
eff↓, targeting autophagy in the tumor environment by CQ may be limited to well-perfused regions but not achieved in acidic regions, predicting possible limitations in efficacy of CQ in antitumor therapies.
other↓, CQ concentrations in the whole-cell lysate were 7-fold lower at pH 6.8 as compared with pH 7.4

2073- HNK,    Honokiol induces apoptosis and autophagy via the ROS/ERK1/2 signaling pathway in human osteosarcoma cells in vitro and in vivo
- in-vitro, OS, U2OS - in-vivo, NA, NA
TumCD↑, honokiol caused dose-dependent and time-dependent cell death in human osteosarcoma cells
TumAuto↑, death induced by honokiol were primarily autophagy and apoptosis.
Apoptosis↑,
TumCCA↑, honokiol induced G0/G1 phase arrest,
GRP78/BiP↑, elevated the levels of glucose-regulated protein (GRP)−78, an endoplasmic reticular stress (ERS)-associated protein
ROS↑, increased the production of intracellular reactive oxygen species (ROS)
eff↓, In contrast, reducing production of intracellular ROS using N-acetylcysteine, a scavenger of ROS, concurrently suppressed honokiol-induced cellular apoptosis, autophagy, and cell cycle arrest.
p‑ERK↑, honokiol stimulated phosphorylation of extracellular signal-regulated kinase (ERK)1/2.
selectivity↑, human fibroblasts showed strong resistance to HNK, the IC50 values for which were 118.9 and 71.5 μM
Ca+2↑, HNK increased intracellular Ca2+ in both HOS and U2OS cells
MMP↓, mitochondrial membrane potential (MMP) sharply decreased following HNK treatment
Casp3↑, HNK markedly activated caspase-3, caspase-9
Casp9↑,
cl‑PARP↑, led to PARP cleavage
Bcl-2↓, expression of Bcl-2, Bcl-xl, and survivin was found to be decreased
Bcl-xL↓,
survivin↓,
LC3B-II↑, HNK increased the level of LC3B-II and Atg5 in HOS and U2OS cells.
ATG5↑,
TumVol↓, HNK at doses of 40 mg/kg resulted in significant decrease in tumor volume and weight, after 7 days of drug administration
TumW↓,
ER Stress↑, ER stress can trigger ROS production through release of calcium

2072- HNK,    Honokiol Suppresses Cell Proliferation and Tumor Migration through ROS in Human Anaplastic Thyroid Cancer Cells
- in-vitro, Thyroid, NA
ROS↑, honokiol induced ROS activation
eff↓, and could be suppressed by pre-treated with an antioxidant agent, N-acetyl-l-cysteine (NAC).

2865- HNK,    Liposomal Honokiol induces ROS-mediated apoptosis via regulation of ERK/p38-MAPK signaling and autophagic inhibition in human medulloblastoma
- in-vitro, MB, DAOY - vitro+vivo, NA, NA
BioAv↓, poor water solubility of HNK results in its low bioavailability, thus limiting its wide use in clinical cancer treatments
BioAv↓, Liposomes can overcome this limitation, and liposomal HNK (Lip-HNK) has promising clinical applications in this aspect
TumCP↓, increased Lip-HNK concentration could inhibit the proliferation of DAOY and D283 cells, without exerting effects on the growth of non-tumor cells
selectivity↑,
P53↑, P53 and P21 proteins (inhibiting cell cycle progression) was increased
P21↑,
CDK4↓, Lip-HNK also downregulated the expression of CDK4 and cyclin D1
cycD1↓,
mtDam↑, Lip-HNK caused apoptosis and death, which, in turn, led to the failure of mitochondrial membrane function
ROS↑, Lip-HNK induced ROS production, which, as hypothesized, was blocked by the ROS scavenger NAC
eff↓, Lip-HNK induced ROS production, which, as hypothesized, was blocked by the ROS scavenger NAC
Casp3↑, caspase-3 sectioned and the Bax protein level increased by Lip-HNK
BAX↑,
LC3II↑, LC3BII protein in the Lip-HNK-treated group was noticeably elevated
Beclin-1↑, Beclin-1 (BECN), Atg7 proteins, and LC3BII were dramatically upregulated in the Lip-HNK-treated cells
ATG7↑,
p62↑, Lip-HNK treatment remarkably increased p62 expression, which was dose-dependent
eff↑, Lip-HNK treatment (20 mg/kg) drastically inhibited tumor growth. The combined treatment of Lip-HNK, Chloroquine , and Carboplatin showed more superior antitumor effects
ChemoSen↑, Lip-HNK alone or combined with chemotherapy (Carboplatin or Etoposide) causes significant regression of orthotopic xenografts
*toxicity↓, We also found that Lip-HNK did not damage the liver and kidney

1919- JG,    The Anti-Glioma Effect of Juglone Derivatives through ROS Generation
- in-vitro, GBM, U87MG - in-vitro, GBM, U251
ROS↑, apoptosis rates were increased after D2 or D3 treatment via ROS generation
Apoptosis↑,
eff↓, The peak of juglone could be detected in fresh solution (Molecular Weight: 174kD), while many unknown compounds could be found, and juglone itself decreased obviously after oxidation (1 week)
eff↓, NAC, a ROS scavenger, reversed the cytotoxic effect, indicating the involvement of ROS generation in the anti-glioma effect of D2 and D3

1922- JG,    Juglone induces apoptosis of tumor stem-like cells through ROS-p38 pathway in glioblastoma
- in-vitro, GBM, U87MG
tumCV↓, inhibit the proliferation of TSCs in glioma by decreasing cell viability
TumCP↓,
ROS↑, juglone could generate ROS significantly
p‑p38↑, increase p38 phosphorylation
eff↓, pretreatment with ROS scavenger or p38-MAPK inhibitor could reverse juglone-induced cytotoxicity
Apoptosis↑, Juglone could induce glioma stem-like cells apoptosis
OS↑, juglone could increase the survival time by about 23.6%(though less significant than TMZ)

1924- JG,    Juglone triggers apoptosis of non-small cell lung cancer through the reactive oxygen species -mediated PI3K/Akt pathway
- in-vitro, Lung, A549
TumCMig↓, substantially suppressed the migration and invasion of these two lung cancer cells
TumCI↓,
TumCCA↑, juglone arrested the cell cycle, induced apoptosis, increased the cleavage of caspase 3
Apoptosis↑,
cl‑Casp3↑,
BAX↑, protein expression of Bax and Cyt c
Cyt‑c↑,
ROS↑, juglone treatment considerably increased intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels
MDA↑,
GPx4↓, suppressed glutathione peroxidase 4 (GPX4) and superoxide dismutase (SOD) activities
SOD↓,
PI3K↓, inhibited the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway
Akt↓,
eff↓, N-acetylcysteine (a ROS scavenger) partially reversed the positive effects of juglone in terms of migration, invasion, ROS production, apoptosis, and PI3K/Akt pathway-associated protein expression

2351- lamb,    Anti-Warburg effect via generation of ROS and inhibition of PKM2/β-catenin mediates apoptosis of lambertianic acid in prostate cancer cells
- in-vitro, Pca, DU145 - in-vitro, Pca, PC3
proCasp3↓, LA exerted cytotoxicity, increased sub G1 population and attenuated the expression of pro-Caspase3 and pro-poly (ADP-ribose) polymerase (pro-PARP) in DU145 and PC3 cells
proPARP↓,
LDHA↓, LA reduced the expression of lactate dehydrogenase A (LDHA), glycolytic enzymes such as hexokinase 2 and pyruvate kinase M2 (PKM2) with reduced production of lactate in DU145 and PC3 cells
Glycolysis↓,
HK2↓,
PKM2↓,
lactateProd↓,
p‑STAT3↓, inhibited the expression of p-STAT3, cyclin D1, C-Myc, β-catenin, and p-GSK3β with the decrease of nuclear translocation of p-PKM2
cycD1↓,
cMyc↓,
β-catenin/ZEB1↓,
p‑GSK‐3β↓,
ROS↑, LA generated ROS in DU145 and PC3
eff↓, while ROS scavenger NAC (N-acetyl L-cysteine) blocked the ability of LA to reduce p-PKM2, PKM2, β-catenin, LDHA, and pro-caspase3 in DU145 cells.

1534- LT,  Api,  EGCG,  RES,    Plant polyphenol induced cell death in human cancer cells involves mobilization of intracellular copper ions and reactive oxygen species generation: a mechanism for cancer chemopreventive action
- in-vitro, Nor, MCF10 - in-vitro, BC, MDA-MB-231 - in-vitro, BC, MDA-MB-468 - in-vitro, PC, Bxpc-3
TumCP↓,
Apoptosis↑,
eff↓, cell death is prevented to a significant extent by cuprous chelator neocuproine and reactive oxygen species scavengers
*toxicity↑, normal breast epithelial cells, cultured in a medium supplemented with copper, become sensitized to polyphenol-induced growth inhibition.
Dose?, apigenin at 5uM promoted growth in MCF10A cells and PC3 cancer cells. This could be because polyphenols at lower concentrations are known to be associated with cell proliferation [21], while behaving as prooxidants at high concentrations
eff↓, Apigenin- and luteolin-induced antiproliferation and apoptosis in cancer cells is inhibited by cuprous chelator but not by iron and zinc chelators
eff↓, EGCG and resveratrol, similar to that of the flavones luteolin and apigenin, also involves the mobilization of endogenous copper and consequent prooxidant effect leading to cell death.

2903- LT,    Luteolin induces apoptosis by ROS/ER stress and mitochondrial dysfunction in gliomablastoma
- in-vitro, GBM, U251 - in-vitro, GBM, U87MG - in-vivo, NA, NA
ER Stress↑, Luteolin induced a lethal endoplasmic reticulum stress response and mitochondrial dysfunction in glioblastoma cells by increasing intracellular reactive oxygen species (ROS) levels.
ROS↑,
PERK↑, Luteolin induced expression of ER stress-associated proteins, including phosphorylation of PERK, eIF2α, ATF4, CHOP and cleaved-caspase 12.
eIF2α↑,
ATF4↑,
CHOP↑,
Casp12↑,
eff↓, Inhibition of ROS production by anti-oxidant N-acetylcysteine could reverse luteolin-induced ER stress and mitochondrial pathways activation as well as apoptosis.
UPR↑, Researches indicate that abnormalities in ER function can cause ER stress, resulting in unfolded protein response (UPR),
MMP↓, integrity of mitochondrial membranes potential decreased in U87MG cells after treatment of 40 uM luteolin
Cyt‑c↑, release of cytochrome C to cytoplasm was elevated in U251MG cells
Bcl-2↓, significantly decreased the expression of anti-apoptotic protein Bcl-2 and increased the expression of pro-apoptotic protein Bax in U251MG and U87MG glioblastoms cells.
BAX↑,
TumCG↓, Luteolin inhibited tumor growth in a xenograft mouse model
Weight∅, luteolin did not affect body weight, alanine aminotransferase (ALT) or aspartate transaminase (AST)
ALAT∅,
AST∅,

1715- Lyco,    Pro-oxidant Actions of Carotenoids in Triggering Apoptosis of Cancer Cells: A Review of Emerging Evidence
- Review, Var, NA
antiOx↑, Carotenoids are well known for their potent antioxidant function in the cellular system.
ROS↑, However, in cancer cells with an innately high level of intracellular reactive oxygen species (ROS), carotenoids may act as potent pro-oxidant molecules and trigger ROS-mediated apoptosis
ChemoSen↑, when carotenoids are delivered with ROS-inducing cytotoxic drugs, they can minimize the adverse effects of these drugs on normal cells by acting as antioxidants without interfering with their cytotoxic effects on cancer cells as pro-oxidants
selectivity↑, In cancer cells with innately high intracellular ROS levels, carotenoids may act as pro-oxidants and trigger ROS-mediated apoptosis of cancer cells.
eff↓, However, under high oxygen tension conditions (e.g., in the lungs of smokers), β-carotene shows tumor-promoting effects.
Casp3↑,
Casp7↑,
Casp9↑,
P53↑,
BAX↑,
DNAdam↑,
mtDam↑, mitochondrial dysfunction
eff↑, Astaxanthin co-treatment with β-carotene and lutein (equimolar 5 µM each)

2533- M-Blu,  PDT,    Methylene blue-mediated photodynamic therapy enhances apoptosis in lung cancer cells
- in-vitro, Lung, A549
MMP↓, MB enhances PDT-induced apoptosis in association with downregulation of anti-apoptotic proteins, reduced mitochondrial membrane potential (MMP), increased phosphorylation of the mitogen-activated protein kinase (MAPK) and the generation of ROS
p‑MAPK↑,
ROS↑,
cl‑PARP↑, n MB-PDT-treated A549 cells, we observed PARP cleavage, procaspase-3 activation, downregulation of the anti-apoptotic proteins Bcl-2 and Mcl-1
Bcl-2↓,
Mcl-1↓,
eff↓, pretreatment of A549 cells with the antioxidant N-acetylcysteine (NAC) followed by MB-PDT resulted in increased cell viability and reduced proteolytic cleavage of PARP.

2450- Matr,    The Promoting Role of HK II in Tumor Development and the Research Progress of Its Inhibitors
- Review, Var, NA
HK2↓, Matrine, an alkaloid extracted from Panax ginseng, also exhibits the ability to suppress HK II expression at a concentration of approximately 2.0 μM.
eff↓, Moreover, when used in combination with the HK II inhibitor LND, matrine demonstrates a synergistic effect in the treatment of myeloid leukemia

1899- MeJa,    Methyl jasmonate induces production of reactive oxygen species and alterations in mitochondrial dynamics that precede photosynthetic dysfunction and subsequent cell death
- in-vitro, NA, NA
ROS↑, MeJa induction of ROS production, which first occurred in mitochondria after 1 h of MeJa treatment and subsequently in chloroplasts by 3 h of treatment,
MMP↓, cessation of mitochondrial movement, the loss of mitochondrial transmembrane potential (MPT),
eff↓, treatment of protoplasts with ascorbic acid or catalase prevented ROS production, organelle change, photosynthetic dysfunction and subsequent cell death.
H2O2?, Generation of H2 O 2,

1778- MEL,    Melatonin: a well-documented antioxidant with conditional pro-oxidant actions
- Review, Var, NA - Review, AD, NA
*ROS↓, melatonin and its metabolic derivatives possess strong free radical scavenging properties.
*antiOx↓, potent antioxidants against both ROS (reactive oxygen species) and RNS (reactive nitrogen species). reduce oxidative damage to lipids, proteins and DNA under a very wide set of conditions where toxic derivatives of oxygen are known to be produced.
ROS↑, a few studies using cultured cells found that melatonin promoted the generation of ROS at pharmacological concentrations (μm to mm range) in several tumor and nontumor cells; thus, melatonin functioned as a conditional pro-oxidant.
selectivity↑, melatonin functions as a prooxidant in cancer cells where it aids in the killing of tumor cells
Dose↑, Melatonin levels in the nucleus and mitochondria reached saturation with a lower dose of 40 mg/kg body weight, with no further accumulation under higher doses of injected melatonin
*mitResp↑, improves mitochondrial respiration and ATP production, thereby reducing electron leakage and ROS generation
*ATP↑,
*ROS↓,
eff↑, melatonin protects mitochondrial function in the brain of Alzheimer's patients through both MT1/MT2 dependent and independent mechanisms
ROS↑, Cytochrome P450 utilizes melatonin as a substrate to generate ROS in mitochondria (melatonin concentration ranges from 0.1 to 10 uM)
Dose↑, melatonin at high concentrations (10-1000uM ) was able to promote ROS generation and lead to Fas-induced apoptosis in human leukemic Jurkat cells. Concentrations of <10uM , melatonin did not induce significant ROS generation in these cancer cells
*toxicity∅, High levels of melatonin (uM to mM) did not cause cytotoxicity in several types of nontumor cells
ROS↑, lower concentrations of melatonin (0.1-10uM ), which exhibited antioxidant action in HepG2 cells within 24 hr, became pro-oxidant after 96 hr of treatment, as indicated by the increase of GSH with 24hr and depletion after 96 hr.
eff↓, Finally, a compound, chlorpromazine, which specifically interrupts the binding of melatonin to calmodulin [188], prevented melatonin-induced AA release and ROS generation;
ROS↝, It remains unknown whether the pro-oxidant action exists in vivo. the vast majority of evidence indicates that melatonin is a potent antioxidant in vivo even at pharmacological concentrations
Dose↑, decline of melatonin production with age may render it more beneficial to supplement melatonin to the aging population to improve health by reducing free radical damage
other↑, melatonin intake has the potential to improve cardiac function, inhibit cataract formation, maintain brain health, alleviate metabolic syndrome, obesity and diabetes,reduce tumorigenesis, protect tissues against ischemia

2383- MET,    Activation of AMPK by metformin promotes renal cancer cell proliferation under glucose deprivation through its interaction with PKM2
- in-vitro, RCC, A498
AMPK↑, In this study, we found that metformin treatment in RCC cells lead to activation of AMPK, which suppressed the cell proliferation under normal condition, but enhanced cell proliferation under glucose deprivation (GD) condition
TumCP↓,
eff↓, but enhanced cell proliferation under glucose deprivation (GD) condition
eff↑, Together, our results suggested that combined of AMPK activation and PKM2 depletion or inhibition can achieve better therapeutic effect for RCC patients.

2238- MF,    Electromagnetic fields act via activation of voltage-gated calcium channels to produce beneficial or adverse effects
- Review, Var, NA
*BMD↑, Therapeutic bone-growth stimulation via Ca2+/nitric oxide/cGMP/protein kinase G. Multiple studies have implicated increased Ca2+ and nitric oxide in the EMF stimulation of bone growth
*VGCC↑, increased VGCC activity following EMF exposure and suggests, therefore, that VGCC stimulation in the plasma membrane is directly produced by EMF exposure.
*Ca+2↑, Other studies, each involving VGCCs, summarized in Table 1, also showed rapid Ca2+ increases following EMF exposure [8, 16, 17, 19, 21].
*NO↑, Multiple studies have implicated increased Ca2+ and nitric oxide in the EMF stimulation of bone growth
*eff↓, Voltage-gated calcium channel stimulation leads to increased intracellular Ca2+, which can act in turn to stimulate the two calcium/calmodulin-dependent nitric oxide synthases and increase nitric oxide.

2236- MF,    Changes in Ca2+ release in human red blood cells under pulsed magnetic field
- in-vitro, Nor, NA
*Ca+2↓, Pulsed magnetic field (PMF) decreases Ca2+ level of inner red blood cell (RBC).
*eff↓, PMF gives RBCs positive effect consistently in Ca2+ level and plays a role in preventing RBC hemolysis from oxidative stress and improving RBCD.
*ROS↓, PMF plays a role in preventing oxidative stress or in restoring oxidative stress on RBCs.

2260- MF,    Alternative magnetic field exposure suppresses tumor growth via metabolic reprogramming
- in-vitro, GBM, U87MG - in-vitro, GBM, LN229 - in-vivo, NA, NA
TumCP↓, proliferation of human glioblastoma multiforme (GBM) cells (U87 and LN229) was inhibited upon exposure to AMF within a specific narrow frequency range, including around 227 kHz.
TumCG↓, daily exposure to AMF for 30 min over 21 days significantly suppressed tumor growth and prolonged overall survival
OS↑,
ROS↑, This effect was associated with heightened reactive oxygen species (ROS) production and increased manganese superoxide dismutase (MnSOD) expression.
SOD2↑,
eff↓, anti-cancer efficacy of AMF was diminished by either a mitochondrial complex IV inhibitor or a ROS scavenger.
ECAR↓, decrease in the extracellular acidification rate (ECAR) and an increase in the oxygen consumption rate (OCR).
OCR↑,
selectivity↑, This suggests that AMF-induced metabolic reprogramming occurs in GBM cells but not in normal cells. Furthermore, in cancer cells, AMF decreased ECAR and increased OCR, while there were no changes in normal cells.
*toxicity∅, did not affect non-cancerous human cells [normal human astrocyte (NHA), human cardiac fibroblast (HCF), human umbilical vein endothelial cells (HUVEC)].
TumVol↓, The results showed a significant treatment effect, as assessed by tumor volume, after conducting AMF treatment five times a week for 2 weeks
PGC-1α↑, Corresponding to the rise in ROS, there was also a time-dependent increase in PGC1α protein expression post-AMF exposure
OXPHOS↑, enhancing mitochondrial oxidative phosphorylation (OXPHOS), leading to increased ROS production
Glycolysis↓, metabolic mode of cancer cells to shift from glycolysis, characteristic of cancer cells, toward OXPHOS, which is more typical of normal cells.
PKM2↓, We extracted proteins that changed commonly in U87 and LN229 cells. Among the individual proteins related to metabolism, pyruvate kinase M2 (PKM2) was found to be inhibited in both.

2252- MF,  HPT,    Cellular Response to ELF-MF and Heat: Evidence for a Common Involvement of Heat Shock Proteins?
- Review, NA, NA
HSPs∅, In some studies, no HSP-related effects were detected after ELF-MF exposure ranging from a few μT to mT and from minutes to 24 h, using different cell types such as astroglial cells (30), HL-60, H9c2, and Girardi heart cells (31, 32), and human kerat
*HSPs↑, exposure has also caused changes in HSP levels in a number of primary or non-transformed (“primary like”) cell lines.
eff↝, The hypothesis that non-stressed cells or organisms are quite responsive to HSP induction after ELF-MF exposure is strengthened by some in vivo studies in invertebrates
*eff↑, ELF-MF Exposure Potentiates the Effects of Heat on HSP Induction
eff↑, Interestingly, when HeLa and HL-60 cancer cells were subjected to comparable magnetic flux densities (10–140 µT), exposure durations (20–30 min) and concurrently heat stressed at 43°C, a stronger HSP70 expression was attained in coexposed cells
eff↓, An interesting finding is that MF exposure provides protection against heat-induced effects such as apoptosis, cell cycle disturbances, or proliferation inhibition in both cell models and in organisms

3477- MF,    Electromagnetic fields regulate calcium-mediated cell fate of stem cells: osteogenesis, chondrogenesis and apoptosis
- Review, NA, NA
*Ca+2↑, When cells are subjected to external mechanical stimulation, voltage-gated ion channels in the cell membrane open and intracellular calcium ion concentration rises
*VEGF↑, BMSCs EMF combined with VEGF promote osteogenesis and angiogenesis
*angioG↑,
Ca+2↑, 1 Hz/100 mT MC4-L2 breast cancer cells EMF lead to calcium ion overload and ROS increased, resulting in necroptosis
ROS↑,
Necroptosis↑,
TumCCA↑, 50 Hz/4.5 mT 786-O cells ELF-EMF induce G0/G1 arrest and apoptosis in cells lines
Apoptosis↑,
*ATP↑, causing the ATP or ADP increases, and the purinergic signal can upregulate the expression of P2Y1 receptors
*FAK↑, Our research team [53] found that ELE-EMF can induce calcium oscillations in bone marrow stem cells, up-regulated calcium ion activates FAK pathway, cytoskeleton enhancement, and migration ability of stem cells in vitro is enhanced.
*Wnt↑, ability of EMF to activate the Wnt10b/β-catenin signaling pathway to promote osteogenic differentiation of cells depends on the functional integrity of primary cilia in osteoblasts.
*β-catenin/ZEB1↑,
*ROS↑, we hypothesize that the electromagnetic field-mediated calcium ion oscillations, which causes a small amount of ROS production in mitochondria, regulates the chondrogenic differentiation of cells, but further studies are needed
p38↑, RF-EMF was able to suppress tumor stem cells by activating the CAMKII/p38 MAPK signaling pathway after inducing calcium ion oscillation and by inhibiting the β-catenin/HMGA2 signaling pathway
MAPK↑,
β-catenin/ZEB1↓,
CSCs↓, Interestingly, the effect of electromagnetic fields is not limited to tumor stem cells, but also inhibits the proliferation and development of tumor cells
TumCP↓,
ROS↑, breast cancer cell lines exposed to ELE-EMF for 24 h showed a significant increase in intracellular ROS expression and an increased sensitivity to further radiotherapy
RadioS↑,
Ca+2↑, after exposure to higher intensity EMF radiation, showed a significant increase in intracellular calcium ion and reactive oxygen species, which eventually led to necroptosis
eff↓, while this programmed necrosis of tumor cells was able to be antagonized by the calcium blocker verapamil or the free radical scavenger n -acetylcysteine
NO↑, EMF can regulate multiple ions in cells, and calcium ion play a key role [92, 130], calcium ion acts as a second messenger that can activate downstream molecules such as NO, ROS

3479- MF,    Evaluation of Pulsed Electromagnetic Field Effects: A Systematic Review and Meta-Analysis on Highlights of Two Decades of Research In Vitro Studies
- Review, NA, NA
*eff↓, evidence suggests that frequencies higher than 100 Hz, flux densities between 1 and 10 mT, and chronic exposure more than 10 days would be more effective in establishing a cellular response
eff↝, undifferentiated PC12 cells are more sensitive to PEMF exposure, while differentiated PC12 cells are more resistant to stress
*Hif1a↑, Retinal pigment epithelial (RPE) cells Frequency of 50 Hz Intensity of 1 mT : HIF-1α, VEGFA, VEGFR-2, CTGF, cathepsin D TIMP-1, E2F3, MMP-2, and MMP-9) increased
*VEGF↑,
*TIMP1↑,
*E2Fs↑,
*MMP2↑,
*MMP9↑,
Apoptosis↑, MCF7, MCF10 Frequencies of 20 and 50 Hz Intensities of 2.0, 3.0, and 5.0 mT Cell apoptosis

3486- MF,    Pulsed electromagnetic field potentiates etoposide-induced MCF-7 cell death
- in-vitro, NA, NA
ChemoSen↑, It is established that pulsed electromagnetic field (PEMF) therapy can enhance the effects of anti-cancer chemotherapeutic agents
tumCV↓, co-treatment with etoposide and PEMFs led to a decrease in viable cells compared with cells solely treated with etoposide.
cl‑PARP↑, PEMFs elevated the etoposide-induced PARP cleavage and caspase-7/9 activation and enhanced the etoposide-induced down-regulation of survivin and up-regulation of Bax.
Casp7↑,
Casp9↑,
survivin↓,
BAX↑,
DNAdam↑, PEMF also increased the etoposide-induced activation of DNA damage-related molecules
ROS↑, the reactive oxygen species (ROS) level was slightly elevated during etoposide treatment and significantly increased during co-treatment with etoposide and PEMF.
eff↓, Moreover, treatment with ROS scavenger restored the PEMF-induced decrease in cell viability in etoposide-treated MCF-7 cells

3457- MF,    Cellular stress response to extremely low‐frequency electromagnetic fields (ELF‐EMF): An explanation for controversial effects of ELF‐EMF on apoptosis
- Review, Var, NA
Apoptosis↑, Ding et al., 8 it was demonstrated that 24‐h exposure to 60 Hz, 5 mT ELF‐EMF could potentiate apoptosis induced by H2O2 in HL‐60 leukaemia cell lines.
H2O2↑,
ROS↑, One of the main mechanisms proposed for defining anticancer effects of ELF‐EMF is induction of apoptosis through upregulation of reactive oxygen species (ROS) which has also been confirmed by different experimental studies.
eff↑, intermittent 100 Hz, 0.7 mT EMF significantly enhanced rate of apoptosis in human hepatoma cell lines pretreated with low‐dose X‐ray radiation.
eff↑, 50 Hz, 45 ± 5 mT pulsed EMF, significantly potentiated rate of apoptosis induced by cyclophosphamide and colchicine
Ca+2↑, Over the past few years, lots of data have shown that ELF‐EMF exposure regulates intracellular Ca2+ level
MAPK↑, Mitogen‐activated protein kinase (MAPK) cascades are among the other important signalling cascades which are stimulated upon exposure to ELF‐EMF in several types of examined cells
*Catalase↑, ELF‐EMF exposure can upregulate expression of different antioxidant target genes including CAT, SOD1, SOD2, GPx1 and GPx4.
*SOD1↑,
*GPx1↑,
*GPx4↑,
*NRF2↑, Activation and upregulation of Nrf2 expression, the master redox‐sensing transcription factor may be the most prominent example in this regard which has been confirmed in a Huntington's disease‐like rat model.
TumAuto↑, Activation of autophagy, ER stress, heat‐shock response and sirtuin 3 expression are among the other identified cellular stress responses to ELF‐EMF exposure
ER Stress↑,
HSPs↑,
SIRT3↑,
ChemoSen↑, Contrarily, when chemotherapy and ELF‐EMF exposure are performed simultaneously, this increase in ROS levels potentiates the oxidative stress induced by chemotherapeutic agents
UPR↑, In consequence of ER stress, cells begin to initiate UPR to counteract stressful condition.
other↑, Since the only proven effects of ELF‐EMF exposure on cells are cellular adaptive responses, ROS overproduction and intracellular calcium overload
PI3K↓, figure 3
JNK↑,
p38↑,
eff↓, ontrarily, when cells are exposed to ELF‐EMF, a new source of ROS production is introduced in cells which can at least partially reverse anticancer effects observed with cell's treatment with melatonin.
*toxicity?, More importantly, ELF‐EMF exposure to normal cells in most cases has shown to be safe and un‐harmful.

520- MF,    Exposure to a 50-Hz magnetic field induced mitochondrial permeability transition through the ROS/GSK-3β signaling pathway
- in-vitro, Nor, NA
*MPT↑, MPT induced by MF exposure was mediated through the ROS/GSK-3β signaling pathway.
*Cyt‑c↑, induced Cyt-c release
*ROS↑, cells exposed to the MF showed increased intracellular reactive oxidative species (ROS) levels and glycogen synthase kinase-3β (GSK-3β) dephosphorylation at 9 serine residue (Ser(9))
*p‑GSK‐3β↑,
*eff↓, attenuated by ROS scavenger (N-acetyl-L-cysteine, NAC) or GSK-3β inhibitor
*MMP∅, no significant effect on mitochondrial membrane potential (ΔΨm)
*BAX↓, Bax declined around 15% which was statistically significant while the total level of Bcl-2 reminded unchanged in cells
*Bcl-2∅,

188- MFrot,  MF,    Spinning magnetic field patterns that cause oncolysis by oxidative stress in glioma cells
- in-vitro, GBM, GBM115 - in-vitro, GBM, DIPG
ROS↑, both GBM and DIPG cells ROS generated by sOMF
SDH↓, Complex II succinate dehydrogenase
eff↓, antioxidant Trolox reverses the cytotoxic effect of sOMF on glioma cells indicating that ROS play a causal role in producing the effect
RPM↑, we hypothesized that the interaction of weak and intermediate strength magnetic fields with the RPM mechanism in the mitochondrial ETC can perturb the electron transfer process (MEP hypothesis) to generate superoxide.
eff↓, We observed that Helmholtz coil did not produce any significant increase in ROS at 2 and 4 h during stimulation or 2 h poststimulation in GBM and DIPG cells
eff↑, oscillating field alone is not sufficient to induce ROS and that the changing angle of the magnetic field axis is also required to achieve this effect.
eff↝, repeated pulse trains rising to and declining from the peak frequency with intervening pauses are sufficient to achieve near maximum level of increase in ROS
eff↝, One spinning magnet or three spinning magnets generate similar cellular ROS levels and the effect of variation of the stimulus off period.
Casp3↑, caspase 3 activation
eff↝, This indicates that the total amount of energy delivered to cancer cells is clearly not the determinant of the potency of stimulation. Instead, it appears that the longer Toff between stimuli of 750 ms in the 4-h stimulation, as opposed to 250 ms in
SOD↓, critical rise in superoxide in two types of human glioma cells (implies SOD capacity exceeded)

184- MFrot,  MF,    Rotating Magnetic Fields Inhibit Mitochondrial Respiration, Promote Oxidative Stress and Produce Loss of Mitochondrial Integrity in Cancer Cells
- in-vitro, GBM, GBM
ROS↑, sOMF
mitResp↓, Inhibit Mitochondrial Respiration
mtDam↑, Produce Loss of Mitochondrial Integrity
Dose↝, Repeated intermittent sOMF was applied for 2 hours at a specific frequency, in the 200-300 Hz frequency range, with on-off epochs of 250 or 500 ms duration.
MMP?, ROS generation has been shown to be driven, in part, by elevated mitochondrial membrane chemiosmotic potential (ΔΨ) and ubiquinol (QH2)
OCR↓, Immediately after cessation of field rotation we observe a loss of mitochondrial integrity (labeled LMI), with a very rapid increase in O2 consumption
mt-H2O2↑, We have previously demonstrated that sOMF treatment of cells generates superoxide/hydrogen peroxide in the mitochondrial matrix
eff↓, we repeated the same experiment in the presence of Trolox, which protects thiols from ROS oxidation (47). sOMF treatment of RLM in State 3u pre-treated with Trolox (15 μM), show minimal inhibition,
SDH↓, SDH Inhibition by sOMF in State 3u RLM Is Caused by ROS Generation
Thiols↓, suggest that thiol oxidation in SDH may result from sOMF.
GSH↓, Glutathione in the mitochondrial matrix can provide some protection from ROS, but after solubilizing the mitochondria, this protection is lost and the SDH becomes more sensitive to sOMF.
TumCD↑, sOMF is highly effective at killing non-dividing GBM cell cultures,
Casp3↑, caspase-3 activation 1 h after sOMF
Casp7↑, rapid activation of caspase-3/7
MPT↑, OMF-treated cell that causes near simultaneous MPT, release of cytochrome c and other apoptosis-inducing factors, resulting in caspase-3/7 activation in these GBM cells.
Cyt‑c↑,
selectivity↑, differential sensitivity to sOMF of cancer cells over ‘normal’ cells becomes apparent. rapid increase in the reactive oxygen species (ROS) in the mitochondria to cytotoxic levels only in cancer cells, and not in normal human cortical neurons
GSH/GSSG↓, increasing GSSG/GSH ratio

2262- MFrot,  MF,    Effects of 0.4 T Rotating Magnetic Field Exposure on Density, Strength, Calcium and Metabolism of Rat Thigh Bones
- in-vivo, ostP, NA
*BMD↑, strong magnetic field (MF) exposure could effectively increase bone density and might be used to treat osteoporosis
*eff↓, calcium supplement tended to increase the indexes of thigh bone density, energy absorption, maximum load, maximum flexibility, and elastic deformation
*ALP↑, alkaline phosphatase (ALP), serum phosphate, and serum calcium were higher in rats exposed to RMF with calcium
*other↑, RMF is in fact capable of increasing density, strength, calcium, and metabolism in bones

2258- MFrot,  MF,    EXTH-68. ONCOMAGNETIC TREATMENT SELECTIVELY KILLS GLIOMA CANCER CELLS BY INDUCING OXIDATIVE STRESS AND DNA DAMAGE
- in-vitro, GBM, GBM - in-vitro, Nor, SVGp12
TumVol↓, GBM patient reversed the progression of his recurrent tumor causing >30% reduction in its contrast-enhanced volume within 4 weeks of treatment
OS↑, Mice with implanted mouse glioma cells in their brains also showed marked reduction in tumor size, increased survival (p< 0.05, n = 10)
γH2AX↑, higher DNA damage (g-H2AX foci) after sOMF treatment with a whole-body stimulation method developed by us
DNAdam↑,
selectivity↑, Normal mice exposed to sOMF for 4 months had no adverse effects on the brain and other organs
ROS↑, sOMF markedly increased reactive oxygen species (ROS) levels in cancer cells leading to the selective death of these cells, while sparing normal neurons and astrocytes
TumCD↑,
eff↑, sOMF exposure for just 2 h resulted in >40% loss of surviving GBM and DIPG cell colonies detected by clonogenic cell survival assay, similar to that produced by 2 Gy radiation dose.
eff↓, This loss was rescued by the antioxidant Trolox

2259- MFrot,  MF,    Method and apparatus for oncomagnetic treatment
- in-vitro, GBM, NA
MMP↓, Oncomagnetic patent Fig 2
Bcl-2↓,
BAX↑,
Bak↑,
Cyt‑c↑,
Casp3↑, caspase staining rises progressively until after 30 min most of the cells fluoresce positive for caspase, revealing activation of this enzyme
Casp9↑,
DNAdam↑,
ROS↑, applying the oscillating magnetic field to the tissue increases the production of reactive oxygen species (ROS )
lactateProd↑,
Apoptosis↑,
MPT↑, opening of the mitochondrial membrane permeability transition pore
*selectivity↑, repetitive magnetic stimulation has shown decreased apoptosis in non -cancerous cells .
eff↑, oncomagnetic therapy may be performed in conjunction with other forms of therapy such as with chemotherapy, other forms of radiative therapy, with drugs and prescriptions, etc
MMP↓, OMF which in turn produces rapidly fluctuating or sustained depolarizations of the mitochondrial membrane potential (MMP) in the tissue .
selectivity↑, Because normal cells have a larger amount of mitochondria, have lower demand for ATP, and are not under stress, disruption of electron flow and small amount of ROS formation and MMP depolarization does not trigger apoptosis
TCA?, decrease in Krebs cycle metabolites
H2O2↑, increase in peroxide levels in GBM cells following stimulation by the system 100 using a rotating magnet
eff↑, combine the administration of BHB , or acetoacetate , or free fatty acid, or branched chain amino acid, or cryptochrome agonist , or MGMT inhibitor, or DNA alkylating agent, or DNA methylating agent, and OMF as a more effective treatment of cancer
*antiOx↑, upregulation of antioxidant mechanisms due to the application of OMFs further protects non -cancerous cells from any ROS -mediated apoptosis
H2O2↑, The experiments showed rapid increases in the levels of superoxide and H2O2 in GBM cells
eff↓, To test whether cell death is caused by the OMF - induced increase in ROS , a potent antioxidant Trolox was used to counteract it, while measuring the decrease in GBM cell count due to 4 h exposure to OMF.
GSH/GSSG↓, GSH/GSSG ratio almost exactly half that seen in control cells
*toxicity∅, No Cytotoxic Effect in Normal Cells
OS↑, OMF -Induced Prolongation of Survival in a Mouse Xenograft Model of GBM

3846- MSM,    Accumulation of methylsulfonylmethane in the human brain: identification by multinuclear magnetic resonance spectroscopy
- Human, NA, NA
*Dose↝, recommended doses of 1-3 g daily
*BBB↑, MSM was detected in all subjects at concentrations of 0.42-3.40 mmole/kg brain and was equally distributed between gray and white matter
*eff↓, a compound with no known medical benefits.

1997- Myr,  QC,    Inhibition of Mammalian thioredoxin reductase by some flavonoids: implications for myricetin and quercetin anticancer activity
- in-vitro, Lung, A549
TrxR↓, Myricetin and quercetin were found to have strong inhibitory effects on mammalian TrxRs with IC50 values of 0.62 and 0.97 micromol/L, respectively
eff↑, Oxygen-derived superoxide anions enhanced the inhibitory effect whereas anaerobic conditions attenuated inhibition.
TumCCA↑, cell cycle was arrested in S phase by quercetin and an accumulation of cells in sub-G1 was observed in response to myricetin.
eff↓, presence of superoxide dismutase diminished the inhibition dramatically
ROS↑, show that ROS played a critical role in the inhibition of TrxR by flavonoids. ...may occur as a result of their easy oxidization to flavonol semiquinone species.

1996- Part,    Critical roles of intracellular thiols and calcium in parthenolide-induced apoptosis in human colorectal cancer cells
- in-vitro, CRC, COLO205
Apoptosis↑, parthenolide has shown to induce apoptosis in cancer cells
GSH↓, Parthenolide rapidly depleted intracellular thiols, including both free glutathione (GSH) and protein thiols.
ROS↑, ncreases in intracellular reactive oxygen species (ROS) and calcium levels
Ca+2↑,
GRP78/BiP↑, Increased expression of GRP78 protein, a marker for endoplasmic reticulum stress was also detected
ER Stress↑,
eff↓, pretreatment with N-acetylcysteine, a precursor of GSH synthesis, protected the cells from parthenolide-induced thiol depletion, ROS production, cytosolic calcium increase and completely blocked parthenolide-induced apoptosis.
eff↑, pretreatment of buthionine sulfoximine, an inhibitor of GSH synthesis sensitized the cell to apoptosis
Thiols↓, Parthenolide rapidly depleted intracellular thiols

1992- Part,    Parthenolide induces ROS-dependent cell death in human gastric cancer cell
- in-vitro, BC, MGC803
TumCCA↑, Parthenolide induced cell cycle arrest at the G1 and S stages.
Casp↑, Parthenolide-induced caspase-dependent apoptosis and necroptosis were caused by the activation of RIP, RIP3 and MLKL
Apoptosis↑,
Necroptosis↑,
RIP1↓,
RIP3↑,
MLKL↑,
ROS↑, MGC-803 cells showed a response to ROS and oxidative stress after PN treatment.
eff↓, ROS and cytotoxicity induced by PN were significantly attenuated by a ROS scavenger catalase.

1989- Part,    Parthenolide and Its Soluble Analogues: Multitasking Compounds with Antitumor Properties
- Review, Var, NA
eff↑, therapeutical potential of PN has been increased by chemical design and synthesis of more soluble analogues including dimethylaminoparthenolide (DMAPT).
NF-kB↓, these compounds not only inhibit prosurvival transcriptional factors such as NF-κB and STATs
STAT↓,
ROS↑, increasing intracellular reactive oxygen species (ROS) production
Inflam↓, anti-inflammatory action of PN has been widely considered a consequence of its inhibitory effect on the transcription factors belonging to NF-κB family
Wnt↓, PN was recently shown to inhibit Wnt signaling by decreasing the levels of the transcription factors TCF4/LEF1
TCF-4↓,
LEF1↓,
GSH↓, Wen et al., who found that PN-induced apoptosis in hepatoma cells was accompanied with depletion of glutathione (GSH), generation of ROS, reduction of mitochondrial transmembrane potential and activation of caspases.
MMP↓,
Casp↑,
eff↓, These effects were effectively abrogated by the antioxidant N-acetyl-l-cysteine (NAC) and enhanced by the GSH synthesis inhibitor buthionine sulfoximine (BSO) confirming the role of oxidative stress in PN-induced apoptosis
CSCs↓, several studies showing the effect of PN in reducing the presence of CSCs in solid and hematological tumors

1986- Part,    Modulation of Cell Surface Protein Free Thiols: A Potential Novel Mechanism of Action of the Sesquiterpene Lactone Parthenolide
- in-vitro, NA, NA
JNK↑, parthenolide mediated activation of JNK
ROS↑, parthenolide induced generation of intracellular reactive oxygen species
eff↓, Parthenolide Cytotoxicity Is Blocked by Thiol Antioxidants
NF-kB↓, parthenolide has been shown to induce malignant cell death by inhibiting NFκB activation and/or activating JNK
Trx↓, thioredoxin pull-down

1984- Part,    Targeting Thioredoxin Reductase by Parthenolide Contributes to Inducing Apoptosis of HeLa Cells
- in-vitro, Cerv, HeLa
AntiCan↑, PTL demonstrates potent anticancer efficacy in numerous types of malignant cells,
TrxR1↓, PTL interacts with both cytosolic thioredoxin reductase (TrxR1) and mitochondrial thioredoxin reductase (TrxR2)
TrxR2↓,
ROS↑, elicit reactive oxygen species-mediated apoptosis in HeLa cells
Apoptosis↑,
eff↓, blocked by pretreatment of the cells with NAC
eff↑, depletion of cellular GSH by pretreatment of the cells with BSO enhances the cytotoxicity of PTL

2069- PB,    Toxic and metabolic effect of sodium butyrate on SAS tongue cancer cells: role of cell cycle deregulation and redox changes
- in-vitro, Tong, NA
TumCG↓, sodium butyrate inhibited the growth of SAS tongue cancer cells by 32% and 53% at concentrations of 1 and 2mM, respectively
ROS↑, These events were concomitant with induction of intracellular reactive oxygen species (ROS) production.
P21↑, An elevation in p21 mRNA and protein level was noted in SAS cells by sodium butyrate.
CycB↓, decline of cyclin Bl, cdc2 and cdc25C mRNA and protein expression in SAS cells was found after exposure to sodium butyrate
cDC2↓,
CDC25↓,
eff↓, Inclusion of N-acetyl-l-cysteine (NAC) (3mM), catalase (1000 U/ml) and dimethylthiourea (DMT, 5mM), and also SOD (500 U/ml) attenuated the sodium butyrate-induced ROS production in SAS cells.
TumCCA↑, sodium butyrate is toxic and inhibits the tongue cancer cell growth via induction of cell cycle arrest and apoptosis
Apoptosis↑,

2077- PB,    Butyrate induces ROS-mediated apoptosis by modulating miR-22/SIRT-1 pathway in hepatic cancer cells
- in-vitro, Liver, HUH7
miR-22↑, Intracellular expression of miR-22 was increased when the Huh 7 cells were incubated with sodium butyrate.
SIRT1↓, Over-expression of miR-22 or addition of sodium butyrate inhibited SIRT-1 expression and enhanced the ROS production
ROS↑, Butyrate induces ROS production
Cyt‑c↑, Butyrate induced apoptosis via ROS production, cytochrome c release and activation of caspase-3
Casp3↑,
eff↓, whereas addition of N-acetyl cysteine or anti-miR-22 reversed these butyrate-induced effects
TumCG↓, sodium butyrate inhibited cell growth and proliferation
TumCP↓,
HDAC↓, induces apoptosis by mediating expression of histone deacetylase (HDAC), SIRT-1, caspase 3, and NFκB
SIRT1↓,
CD44↓, Previously it was shown that butyrate significantly inhibited CD44 expression, thereby inhibiting the metastatic ability of the human colon carcinoma cells [6].
proMMP2↓, Prolonged butyrate treatment inhibited the pro-MMP-2 activation and tumor cell migration potential of HT 1080 tumor cells [7].
MMP↓, Butyrate alters mitochondrial membrane potential (ψm)
SOD↓, Butyrate inhibits super oxide dismutase

2430- PBG,    The cytotoxic effects of propolis on breast cancer cells involve PI3K/Akt and ERK1/2 pathways, mitochondrial membrane potential, and reactive oxygen species generation
- in-vitro, BC, MDA-MB-231
TumCP↓, CP extract exhibited antiproliferative and cytotoxic effects on MDA MB-231 cells, what may be probably related to PI3K/Akt and ERK1/2 pathways.
TP53↓, decreased expression of apoptosis-related genes (TP53, CASP3, BAX and P21)
Casp3↓,
BAX↓,
P21↓,
ROS↑, These results suggested that CP cytotoxic effects on MDA MB-231 cells might be associated with the intracellular ROS production
eff↓, CP-induced ROS generation was reduced after cotreatment with the antioxidant NAC, which increased the percentage of viable cells, suggesting that CP-induced necrotic-related cell death could be associated with ROS production
MMP↓, Necrosis death is associated with mitochondrial dysfunction and our propolis sample reduced the MMP and increased LDH levels.
LDH↑,
ATP↓, rupture of mitochondrial membrane, loss of adenosine triphosphate (ATP),
Ca+2↑, excessive ROS production, intracellular [Ca+2] elevation, osmotic shock,

1666- PBG,    Molecular and Cellular Mechanisms of Propolis and Its Polyphenolic Compounds against Cancer
- Review, Var, NA
ChemoSen↑, Ingredients from propolis also ”sensitize“ cancer cells to chemotherapeutic agents
TumCCA↑, cell-cycle arrest and attenuation of cancer cells proliferation
TumCP↓,
Apoptosis↑,
antiOx↓, behave as antioxidants against peroxyl and hydroxyl radicals,
ROS↑, whereas prooxidant activity is observed in the presence of Cu2+.
COX2↑, Propolis, as well as flavonoids derived from propolis, such as galangin, is a potent COX-2 inhibitor
ER(estro)↓, Some flavonoids from propolis, such as galangin, genistein, baicalein, hesperetin, naringenin, and quercetin, suppressed the proliferation of an estrogen receptor (ER)
cycA1↓, by suppressing expressions of cyclin A, cyclin B, and Cdk2 and by stopping proliferation at the G2 phase, by increasing levels of p21 and p27 proteins, and through the inhibition of telomerase reverse transcriptase (hTERT),
CycB↓,
CDK2↓,
P21↑,
p27↑,
hTERT↓, leukemia cells, propolis successfully reduced hTERT mRNA expression
HDAC↓, by suppressing expressions of cyclin A, cyclin B, and Cdk2 and by stopping proliferation at the G2 phase, by increasing levels of p21 and p27 proteins, and through the inhibition of telomerase reverse transcriptase (hTERT),
ROS⇅, Mexican propolis, demonstrated both pro- and anti-inflammatory effects, depending on the dose applied
Dose?, Mexican propolis, demonstrated both pro- and anti-inflammatory effects, depending on the dose applied
ROS↓, By scavenging free radicals, chelating metal ions (mainly iron and copper), and stimulating endogenous antioxidant defenses, propolis and its flavonoids directly attenuate the generation of ROS
ROS↑, Romanian propolis [99], exhibits prooxidant properties at high concentrations, by mobilizing endogenous copper ions and DNA-associated copper in cells.
DNAdam↑, propolis, i.e., its polyphenolic components, may induce DNA damage in the presence of transition metal ions.
ChemoSen↑, Algerian propolis + doxorubicin decreased cell viability, prevented cell proliferation and cell cycle progression, induced apoptosis by activating caspase-3 and -9 activities, and increased the accumulation of chemotherapeutic drugs in MDA-MB-231 cel
LOX1↓, propolis components inhibited the LOX pathway
lipid-P↓, Croatian propolis improved psoriatic-like skin lesions induced by irritant agents n-hexyl salicylate or di-n-propyl disulfide by decreasing the extent of lipid peroxidation
NO↑, Taken together, propolis may increase the phagocytic index, NO production, and production of IgG antibodies
Igs↑,
NK cell↑, propolis treatment for 3 days increases the cytotoxic activity of NK cells against murine lymphoma.
MMPs↓, extracts of propolis containing artepillin C and CAPE decreased the formation of new vessels and expression of MMPs and VEGF in various cancer cells
VEGF↓,
Hif1a↓, Brazilian green propolis inhibit the expression of the hypoxia-inducible factor-1 (HIF-1) protein and HIF-1 downstream targets such as glucose transporter 1, hexokinase 2, and VEGF-A
GLUT1↓,
HK2↓,
selectivity↑, Portuguese propolis was selectively toxic against malignant cells.
RadioS↑, propolis increased the lifespan of mice that received the radiotherapy with gamma rays
GlucoseCon↓, Portuguese propolis disturbed the glycolytic metabolism of human colorectal cancer cells, as evidenced by a decrease in glucose consumption and lactate production
lactateProd↓,
eff↓, Furthermore, different pesticides or heavy metals can be found in propolis, which can cause unwanted side effects.
*BioAv↓, Due to the low bioavailability and clinical efficacy of propolis and its flavonoids, their biomedical applications remain limited.

1648- PBG,    Contribution of Green Propolis to the Antioxidant, Physical, and Sensory Properties of Fruity Jelly Candies Made with Sugars or Fructans
- Review, Nor, NA
Dose∅, recommended dosage as yet, although it is presumed that one ranging from 260 to 2870 mg/day/person would be safe in humans,
Dose∅, Brazilian green propolis, nutraceutical dosages would be around 500 mg/day/person
eff↓, Brazilian green propolis found that wax melts between 60 and 70 °C, while propolis chemical components degraded in the range of 100–200 °C
antiOx↑, antioxidant effects of propolis polyphenols

1674- PBG,  SDT,  HPT,    Study on the effect of a triple cancer treatment of propolis, thermal cycling-hyperthermia, and low-intensity ultrasound on PANC-1 cells
- in-vitro, PC, PANC1 - in-vitro, Nor, H6c7
tumCV↓, cell viability of a human cancer cell line PANC-1 decreased to a level 80% less than the control
ROS↑, triple treatment showed a significant accumulation of the intracellular ROS (up to a 2.1-fold increase)
eff↑, combination of TC-HT and US also promotes the anticancer effect of the heat-sensitive chemotherapy drug cisplatin on PANC-1 cells
Dose∅, moderate propolis concentration 0.3%, 10-cycles TC-HT and 2.25 MHz US with intensity 0.3 W/cm2 and duration 30 minutes were chosen to avoid the thermotoxicity on PANC-1 cells
selectivity↑, Moreover, normal cells such as the human skin cells Detroit 551 (Figure 1D) and human pancreatic duct cells H6c7 (Figure 1E) were not significantly affected by the triple treatment as well as all the other treatments.
MMP↓, ratio of the cells exhibiting MMP loss was significantly promoted to 23.3% after the double treatment of propolis + TC-HT, and it was further elevated significantly to 34.7% by employing the triple treatment.
mtDam↑, hence caused more mitochondrial dysfunction
cl‑PARP↑, PARP cleavage was further promoted significantly to a 6.2-fold increase by US in the triple treatment
p‑ERK↓, the p-ERK level was suppressed by propolis + TC-HT treatment (0.30-fold decrease), and was further down-regulated when US was introduced in the triple treatment (0.15-fold decrease)
p‑JNK↑, p-JNK and p-p38 levels both exhibited a reverse performance, which were promoted the most in the triple treatment (8.7-fold and 9.2-fold increase, respectively)
p‑p38↑,
eff↓, inhibitory effect of the triple treatment was restored by NAC
ChemoSen↑, cisplatin + TC-HT treatment significantly elevated PARP cleavage to a 3.20-fold increase. This elevation was further increased with the help of US (5.82-fold increase).

1231- PBG,    Caffeic acid phenethyl ester inhibits MDA-MB-231 cell proliferation in inflammatory microenvironment by suppressing glycolysis and lipid metabolism
- in-vitro, BC, MDA-MB-231
TumCP↓,
TumCMig↓,
TumCI↓,
MMP↓,
TLR4↓,
TNF-α↓,
NF-kB↓,
IL1β↓,
IL6↓,
IRAK4↓,
GLUT1↓,
GLUT3↓,
HK2↓,
PFK↓,
PKM2↓,
LDHA↓,
ACC↓,
FASN↓,
eff↓, After adding the glycolysis inhibitor 2-deoxy-D-glucose (2-DG), the inhibitory effects of CAPE on cell viability and migration were not significant when compared with the LPS group.

1767- PG,    Propyl gallate induces cell death in human pulmonary fibroblast through increasing reactive oxygen species levels and depleting glutathione
- in-vitro, Nor, NA
*ROS↑, PG (100–800 μM) increased the levels of total ROS and O2·− at early time points of 30–180 min and 24 h
*GSH↓, whereas PG (800–1600 μM) increased GSH-depleted cell number at 24 h and reduced GSH levels at 30–180 min.
*SOD↓, PG downregulated the activity of superoxide dismutase (SOD) and upregulated the activity of catalase in HPF cells
*Catalase↓,
eff↓, NAC treatment attenuated HPF cell death and MMP (ΔΨm) loss induced by PG, accompanied by a decrease in GSH depletion

1950- PL,    Increased Expression of FosB through Reactive Oxygen Species Accumulation Functions as Pro-Apoptotic Protein in Piperlongumine Treated MCF7 Breast Cancer Cells
- in-vitro, BC, MCF-7 - in-vitro, Lung, A549
selectivity↑, Piperlongumine (PL), a natural alkaloid compound isolated from long pepper (Piper longum), can selectively kill cancer cells, but not normal cells,
ROS↑, by accumulation of reactive oxygen species (ROS)
SETBP1↓, PL downregulates SETDB1 expression
cl‑Casp9↑, enhanced caspase 9 dependent-PARP cleavage during PL-induced cell death.
eff↓, ROS inhibitor NAC (N-acetyl cysteine) recovered SETDB1 expression decreased by PL.
FOSB↑, Decreased SETDB1 expression induced transcriptional activity of FosB during PL treatment. PL treatment dramatically increased FosB promoter activity up to 9-fold

1939- PL,    Piperlongumine selectively kills hepatocellular carcinoma cells and preferentially inhibits their invasion via ROS-ER-MAPKs-CHOP
- in-vitro, HCC, HepG2 - in-vitro, HCC, HUH7 - in-vivo, NA, NA
TumCMig↓, PL specifically suppressed HCC cell migration/invasion via endoplasmic reticulum (ER)-MAPKs-CHOP signaling pathway
TumCI↓,
ER Stress↑, Piperlongumine induces ER stress-responses which preferentially suppresses HCC cell migration/invasion
selectivity↑, PL selectively killed HCC cells but not normal hepatocytes with an IC50 of 10-20 μM while PL at much lower concentrations only suppressed HCC cell migration/invasion
tumCV↓,
ROS↑, Piperlongumine induces ROS accumulation to exert its anti-cancer effects on HCC cells
GSH↓, Consistently, intracellular glutathione (GSH) levels were significantly reduced in HepG2 or Huh7 cells at 1 h of PL treatment
eff↓, Pre-treatment of NAC or GSH completely reversed PL-induced cell death in Huh7 cells (Fig. 3E) and HepG2 cells
Ca+2↑, concentration of cytoplasmic free Ca2+ was prominently increased at 3 h of PL treatment in a dose-dependent manner (0-20 μM)
MAPK↑, Piperlongumine activates MAPKs signaling pathways which preferentially suppress HCC migration
CHOP↑, These evidences demonstrated that PL activated ER-MAPKs-CHOP axis signaling pathways via ROS-dependent mechanisms.
Dose↝, Notably, PL at a much lower concentration (1.5 mg/kg) showed a comparable anticancer effect in HCC-bearing mice and increasing PL concentration did not significantly enhance its anticancer effects

1940- PL,    Piperlongumine Inhibits Migration of Glioblastoma Cells via Activation of ROS-Dependent p38 and JNK Signaling Pathways
- in-vitro, GBM, LN229 - in-vitro, GBM, U87MG
ROS↑, demonstrated that PL induced ROS accumulation in scratched LN229 cells.
GSH↓, reduced glutathione
p38↑, activated p38 and JNK, increased IκBα
JNK↑,
IKKα↑,
NF-kB↓, suppressed NFκB in LN229 cells after scratching
eff↓, All the biological effects of PL in scratched LN229 cells were completely abolished by the antioxidant N-acetyl-L-cysteine (NAC).

1944- PL,    Piperlongumine, a Novel TrxR1 Inhibitor, Induces Apoptosis in Hepatocellular Carcinoma Cells by ROS-Mediated ER Stress
- in-vitro, HCC, HUH7 - in-vitro, HCC, HepG2
ER Stress↑, PL induces a lethal endoplasmic reticulum (ER) stress response in HCC cells
TrxR1↓, PL treatment reduces TrxR1 activity and tumor cell burden in vivo
ROS↑, and increasing intracellular ROS levels
eff↓, Interestingly, pretreatment with NAC, a specific ROS inhibitor, for 2 h apparently suppressed PL-induced increases in ROS levels
Bcl-2↓, PL treatment decreased the levels of the antiapoptotic proteins Bcl-2 and procaspase3 and increased the levels of the proapoptotic proteins Bax and cleaved caspase-3 in a dose-dependent manner.
proCasp3↓,
BAX↓,
cl‑Casp3↑,
TumCCA↑, PL Induces ROS-Dependent G2/M Cell Cycle Arrest in HCC Cells
p‑PERK↑, PL increased the expression of p-PERK and ATF4 in a dose-dependent manner.
ATF4↑,
TumCG↓, PL Inhibits HUH-7 Xenograft Tumor Growth Accompanied by Increased ROS Levels and Decreased Trxr1 Activity
lipid-P↑, PL treatment increased the levels of the product of lipid peroxidation (MDA) in tumor tissues ( Figure 6H ), suggesting increased ROS levels
selectivity↑, In normal cells, TrxR1 can protect against oxidant stress

1947- PL,    Piperlongumine as a direct TrxR1 inhibitor with suppressive activity against gastric cancer
- in-vitro, GC, SGC-7901 - in-vitro, GC, NA
TrxR1↓, In vivo, PL treatment markedly reduces the TrxR1 activity and tumor cell burden
ROS↑, PL may interact with the thioredoxin reductase 1 (TrxR1), an important selenocysteine (Sec)-containing antioxidant enzyme, to induce reactive oxygen species (ROS)-mediated apoptosis in human gastric cancer cells
ER Stress↑, PL induces a lethal endoplasmic reticulum stress and mitochondrial dysfunction in human gastric cancer cells
mtDam↑,
selectivity↑, known to selectively kill tumor cells while sparing their normal counterparts. PL treatment did not cause a significant increase in ROS levels in normal GES-1 cells
NO↑, we found that nitric oxide was also induced by PL in gastric cancer cells
TumCCA↑, PL treatment significantly induced G2/M cell cycle arrest in human gastric cancer SGC-7901, BGC-823 and KATO III cells.
mt-ROS↑, mitochondrial ROS, were involved in the PL-induced cell death in gastric cancer cells.
Casp9↑, Notably, caspase-9 activity was significantly elevated after PL treatment in SGC-7901 cells
Bcl-2↓, PL treatment dose-dependently decreased the expression of antiapoptotic proteins Bcl-2 and Bcl-xL, but induced the cleavage of poly (ADP-ribose) polymerase (PARP)
Bcl-xL↓,
cl‑PARP↑,
eff↓, Pre-incubation with GSH attenuated these effects confirming their linkage to PL-induced oxidative stress
lipid-P↑, PL dose-dependently increased the level of lipid peroxidation product (MDA), a marker of ROS, in tumor tissues

2958- PL,    Natural product piperlongumine inhibits proliferation of oral squamous carcinoma cells by inducing ferroptosis and inhibiting intracellular antioxidant capacity
- in-vitro, Oral, HSC3
TumCP↓, proliferation rate of PL-treated OSCC cells were decreased in a dose- and time-dependent manner.
lipid-P↑, Lipid peroxidation (LPO) and intracellular reactive oxygen species (ROS) were accumulated after PL treatment.
ROS↑,
DNMT1↑, expression of DMT1 increased, and the expression of FTH1, SLC7A11 and GPX4 decreased.
FTH1↓,
GPx4↓,
eff↓, effect of PL on OSCC cells can be reversed by iron scavengers and antioxidants
GSH↓, PL can inhibit the synthesis of intracellular GSH to induce ferroptosis
Ferroptosis↑,
MDA↓, content of MDA decreased

2957- PL,    Piperlongumine Induces Cell Cycle Arrest via Reactive Oxygen Species Accumulation and IKKβ Suppression in Human Breast Cancer Cells
- in-vitro, BC, MCF-7
TumCP↓, We found that PL decreased MCF-7 cell proliferation and migration.
TumCMig↓,
TumCCA↑, PL induced G2/M phase cell cycle arrest.
ROS↑, PL induced intracellular reactive oxygen species (hydrogen peroxide) accumulation and glutathione depletion
H2O2↑,
GSH↓,
IKKα↓, PL-mediated inhibition of IKKβ expression decreased nuclear translocation of NF-κB p65.
NF-kB↓,
P21↑, PL significantly increased p21 mRNA levels.
eff↓, PL significantly decreased cellular GSH levels, while in cells pre-treated with NAC, the GSH levels were similar to those observed in control cells

2949- PL,    Piperlongumine selectively kills glioblastoma multiforme cells via reactive oxygen species accumulation dependent JNK and p38 activation
- in-vitro, GBM, LN229 - in-vitro, GBM, U87MG
selectivity↑, Piperlongumine (PL) selectively kills GBM cells but not normal astrocytes.
ROS↑, PL kills GBM cells via ROS accumulation
JNK↑, JNK and p38 activation contributes to PL’s cytotoxicity in GBM cells.
p38↑,
GSH↓, PL elevated ROS prominently and reduced glutathione levels in LN229 and U87 cells.
eff↓, Antioxidant N-acetyl-l-cysteine (NAC) completely reversed PL-induced ROS accumulation and prevented cell death in LN229 and U87 cells.

2944- PL,    Piperlongumine, a Potent Anticancer Phytotherapeutic, Induces Cell Cycle Arrest and Apoptosis In Vitro and In Vivo through the ROS/Akt Pathway in Human Thyroid Cancer Cells
- in-vitro, Thyroid, IHH4 - in-vitro, Thyroid, 8505C - in-vivo, NA, NA
ROS↑, it is selectively toxic to cancer cells by generating reactive oxygen species (ROS)
selectivity↑,
tumCV↓, Cell viability, colony formation, cell cycle, apoptosis, and cellular ROS induction.
TumCCA↑,
Apoptosis↑,
ERK↑, activation of Erk and the suppression of the Akt/mTOR pathways through ROS induction were seen in cells treated with PL
Akt↓,
mTOR↓,
neuroP↑, neuroprotective, and anticancer properties
Bcl-2↓, induces the downregulation of Bcl2 expression and the activation of caspase-3, poly (ADP-ribose) polymerase (PARP), and JNK
Casp3↑,
PARP↑,
JNK↑,
*toxicity↓, several whole-animal models, and it is highly safe when used in vivo
eff↓, Pre-treatment with N-acetylcysteine (NAC; a selective ROS scavenger) significantly reduced PL-mediated ROS activation
TumW↓, tumor weight in the PL (10 mg/kg) treatment group significantly decreased when compared with that in the control group

2940- PL,    Piperlongumine Induces Reactive Oxygen Species (ROS)-dependent Downregulation of Specificity Protein Transcription Factors
- in-vitro, PC, PANC1 - in-vitro, Lung, A549 - in-vitro, Kidney, 786-O - in-vitro, BC, SkBr3
ROS↑, characterized as an inducer of reactive oxygen species (ROS)
TumCP↓, 5-15 μM piperlongumine inhibited cell proliferation and induced apoptosis and ROS,
Apoptosis↑,
eff↓, these responses were attenuated after cotreatment with the antioxidant glutathione
Sp1/3/4↓, Piperlongumine also downregulated expression of Sp1, Sp3, Sp4
cycD1↓, and several pro-oncogenic Sp-regulated genes including cyclin D1, survivin, cMyc, epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (cMet)
survivin↓,
cMyc↓,
EGFR↓,
cMET↓,

2964- PL,    Preformulation Studies on Piperlongumine
- Analysis, Nor, NA
*BioAv↓, The solubility of piperlongumine in water was found to be approximately 26 μg/ml.
*BioAv↑, Using 10% polysorbate 80 as a surfactant resulted in a 27 fold increase in solubility.
*other↝, maximum stability around pH 4. It was estimated that it would take approximately 17 weeks for piperlongumine to degrade by 10% at 25°C, pH 4.
*eff↓, piperlongumine showed marked photo-degradation upon exposure to an ultraviolet light source, especially in aqueous media.

2004- Plum,    Plumbagin Inhibits Proliferative and Inflammatory Responses of T Cells Independent of ROS Generation But by Modulating Intracellular Thiols
- in-vivo, Var, NA
TumCP↓, Plumbagin inhibited activation, proliferation, cytokine production, and graft-versus-host disease in lymphocytes and inhibited growth of tumor cells
TumCG↓,
NF-kB↓, by suppressing nuclear factor-κB (NF-κB)
ROS↑, Plumbagin was also shown to induce reactive oxygen species (ROS) generation in tumor cells via an unknown mechanism
GSH↓, Plumbagin depleted glutathione (GSH) levels that led to increase in ROS generation
eff↓, production by plumbagin was abrogated by thiol antioxidants but not by non-thiol antioxidants confirming that thiols but not ROS play an important role in biological activity of plumbagin.
i-Thiols↓, Plumbagin depleted intracellular thiols (mainly GSH)
GSH/GSSG↓, plumbagin also induced GSH to GSSG conversion
*GSH↓, In this report, for the first time we show GSH depletion as a source of ROS generation in normal lymphocytes following plumbagin treatment.
*ROS↑, plumbagin-induced increase in ROS levels in lymphocytes

2006- Plum,    Plumbagin induces apoptosis in human osteosarcoma through ROS generation, endoplasmic reticulum stress and mitochondrial apoptosis pathway
- in-vitro, OS, MG63 - in-vitro, Nor, hFOB1.19
tumCV↓, Plumbagin reduced cell viability in osteosarcoma cells but not normal bone cells
selectivity↑,
mtDam↑, Plumbagin induced cell apoptosis by mitochondrial dysfunction, which in turn promoted Ca2+ release and endoplasmic reticulum (ER)‑stress
Ca+2↓,
ER Stress↑,
ROS↑, plumbagin improved reactive oxygen species (ROS) generation
Casp3↑, apoptotic cascades activated caspase‑3 and caspase‑9 to elicit apoptosis response
Casp9↑,
Apoptosis↑,
eff↓, Moreover, plumbagin-induced apoptosis was reversed by pretreating with ROS scavenger N-acetyl cysteine (NAC), NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) and H2O2 scavenging enzyme (catalase)

2005- Plum,    Plumbagin induces apoptosis in lymphoma cells via oxidative stress mediated glutathionylation and inhibition of mitogen-activated protein kinase phosphatases (MKP1/2)
- in-vivo, Nor, EL4 - in-vitro, AML, Jurkat
JNK↑, Plumbagin induced persistent activation of JNK
Cyt‑c↑, plumbagin induced cytochrome c release, FasL expression and Bax levels via activation of JNK pathway
FasL↑,
BAX↑,
ROS↑, plumbagin has been reported to induce ROS in normal as well as in tumor cells
*ROS↑, induce ROS in normal as well as in tumor cells
MKP1↓, plumbagin induced oxidative stress may suppress MKP activity in lymphoma cells leading to sustained JNK activation resulting in apoptosis.
MKP2↓,
selectivity∅, Plumbagin induced cell death in EL4(normal) cells and Jurkat cells
tumCV↑, cell viability dramatically decreased with increasing concentrations of plumbagin (0.05-2.5uM) when incubated for 24 or 48 h
Cyt‑c↑, Bax dependent cytochrome c release and apoptosome complex formation is followed by the cleavage of pro-caspase-3
Casp3↑,
GSH/GSSG↓, progressive decrease in GSH/GSSG ratio in tumor cells following plumbagin treatment
ROS↑, simultaneous increase in the levels of intracellular ROS was observed in both these cell lines which remained high up to 4 h indicating an increase in oxidative stress in tumor cells
mt-ROS↑, While we observed low basal mtROS levels in untreated cells, plumbagin treatment resulted in a significant increase in mtROS levels
*ROS↑, both cell lines, meaning normal EL4 cells too
eff↓, NAC, GSH and PEG-catalase were able to abrogate plumbagin induced ROS and cell death.

2341- QC,    Quercetin suppresses the mobility of breast cancer by suppressing glycolysis through Akt-mTOR pathway mediated autophagy induction
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231 - in-vivo, NA, NA
MMP2↓, quercetin treatment down-regulated the expression of cell migration marker proteins, such as matrix metalloproteinase 2 (MMP-2), MMP-9 and vascular endothelial growth factor (VEGF).
MMP9↓, level of MMP-2, MMP-9 and VEGF was all strongly cut down by quercetin treatment compared with control group
VEGF↓,
Glycolysis↓, quercetin successfully blocked cell glycolysis by inhibiting the level of glucose uptake and the production of lactic acid
lactateProd↓,
PKM2↓, and also decreased the level of glycolysis-related proteins Pyruvate kinase M2 (PKM2), Glucose transporter1(GLUT1) and Lactate dehydrogenase A (LDHA).
GLUT1↓,
LDHA↓,
TumAuto↑, quercetin induced obvious autophagy via inactivating the Akt-mTOR pathway
Akt↓,
mTOR↓,
TumMeta↓, Quercetin suppressed the progression of breast cancer by inhibiting tumor metastasis and glycolysis in vivo
MMP3↓, quercetin effectively suppressed the invasion and migration ability of breast cancer cells through suppressing the expression of MMP-3, MMP-9 and VEGF,
eff↓, down-regulating the expression of PKM2, which regulated the final step of glycolysis, could effectively enhance the chemotherapeutic effect of THP
GlucoseCon↓, we found that quercetin effectively suppressed the level of glucose uptake and the production of lactic acid, and also down-regulated the expression of glycolysis-related proteins PKM2, LDHA and GLUT1,
lactateProd↓,
TumAuto↑, quercetin treatment induced obvious autophagy in MCF-7 and MDA-MB-231 cells via inactivating the Akt-mTOR pathway
LC3B-II↑, showing obvious conversion of LC3B-I to LC3B-II

1742- RosA,    Rosmarinic acid, a natural polyphenol, has a potential pro-oxidant risk via NADH-mediated oxidative DNA damage
- Analysis, Var, NA
ROS↑, RA plus Cu(II), but not Fe(III), significantly increased 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodG) formation, an indicator of oxidative DNA damage, in calf thymus DNA
eff↑, RA plus Cu(II) caused DNA cleavage, which was enhanced by piperidine treatment, suggesting that RA causes not only DNA strand breakage but also base modification.
eff↑, metals such as copper and iron could be associated with the pro-oxidant risk of RA;
eff↑, Interestingly, the addition of NADH markedly enhanced 8-oxodG formation by RA plus Cu(II) (approximately 30-fold increase at 0.1–0.5 µM) (Fig. 1B). On the other hand, RA plus Fe(III) did not increase 8-oxodG formation even in the presence of NADH
eff↑, RA caused DNA cleavage in a concentration-dependent manner, and piperidine treatment enhanced DNA cleavage.
eff↓, Catalase, an H2O2 scavenger, and bathocuproine, a Cu(I)-specific chelator [26], inhibited DNA damage induced by RA plus Cu(II)
Dose↝, The maximum serum concentration of RA was reported to reach approximately 0.16 µM after the administration of plant extracts containing 500 mg of RA in humans
Dose↝, In this study, 0.1 µM RA induced oxidative DNA damage in the presence of physiologically relevant concentrations of Cu(II) (20 µM) [35] and NADH (100 µM)

1388- Sco,    Scoulerine promotes cell viability reduction and apoptosis by activating ROS-dependent endoplasmic reticulum stress in colorectal cancer cells
- in-vitro, CRC, NA
tumCV↓,
Apoptosis↑,
Casp3↑,
Casp7↑,
BAX↑,
Bcl-2↓,
ROS↑,
GSH↓,
SOD↓,
ER Stress↑,
GRP78/BiP↑,
CHOP↑,
eff↓, blocking ROS production by ROS scavenger N-acetyl-cysteine (NAC) attenuated scoulerine-induced ER stress.

2548- SDT,    Sonoporation, a Novel Frontier for Cancer Treatment: A Review of the Literature
- Review, Var, NA
sonoP↑, Sonoporation has garnered significant attention for its potential to temporarily permeabilize cell membranes through the application of ultrasound waves, thus enabling an efficient cellular uptake of molecules
Dose↝, When, however, the acoustic intensity (ISATA) exceeds a certain threshold, typically 5 W/cm2 [8,9], the microbubble collapses forcefully, mechanically breaking the membrane;
eff↓, very low-intensity ultrasound (VLIUS) to tumor and normal cells, revealing that a specific VLIUS intensity (120 mW/cm2) significantly enhanced the uptake of nanoparticles and improved the delivery of the chemotherapy drug trabectedin in cancer cells
Dose↝, nanoparticles were combined with low-intensity focused ultrasound with a frequency of 1.0 MHz, a duty cycle of 50%, and an acoustic intensity of 2000, 2400, and 2800 mW/cm2
BioEnh↑,
toxicity↝, Ultrasound, especially at high acoustic intensities, can induce collateral damages that are not easy to predict; this is why low-intensity applications must be promoted.

1706- Se,    Selenium in Prostate Cancer: Prevention, Progression, and Treatment
- Review, Pca, NA
Risk∅, randomized controlled studies have shown that selenium supplementation does not prevent prostate cancer (HR: 0.95; 95% CI 0.80–1.13).
ChemoSen↑, In the context of combinatorial therapy, selenium has demonstrated promising synergistic potential in the treatment of prostate cancer.
Risk↓, Moreover, there is increasing evidence suggesting that selenium can serve as a preventive agent, and the levels of selenium in the bloodstream may be linked to the development of prostate cancer
toxicity↝, Interestingly, both low and high levels of selenium have shown potential implications.
Risk↑, Generally, lower serum selenium status has been correlated with an increased risk of cancer.
eff↑, Furthermore, foundational studies have proposed that antioxidants, such as vitamin E and lycopene [50], may enhance the effectiveness of selenium in preventing the formation of mammary tumors.
*toxicity↑, selenium supplementation after diagnosis and found that supplementation of 140 μg/day or more following a nonmetastatic prostate cancer diagnosis increased prostate cancer mortality.
RadioS↑, Sodium selenite, for instance, has demonstrated a significant enhancement of the radiosensitizing effect in both HI–LAPC-4 and PC-3 xenograft tumors
eff↓, Additionally, another study [59] provided valuable evidence indicating that prostate cancer patients with low levels of selenium and lycopene are more susceptible to DNA damage induced by ionizing radiation.
eff↑, Husbeck et al. highlighted that selenite increases sensitivity to gamma radiation in prostate cancer by reducing the ratio of GSH:GSSG
ChemoSen↑, while selenium supplementation alone did not demonstrate a positive effect on prostate cancer progression, it shows promise in enhancing the efficacy of chemotherapy and radiotherapy while mitigating their associated side effects during cancer treatm
ChemoSideEff↓,

1699- Se,    Vegetarianism and colorectal cancer risk in a low-selenium environment: effect modification by selenium status? A possible factor contributing to the null results in British vegetarians
- Analysis, CRC, NA
Dose↑, a food-based recommendation is desirable and Brazil nuts have been shown to improve Se status
eff↓, undoubtedly Se is a micronutrient of concern in plant-based diets in Se-poor areas
Dose↓, A dramatic decrease in the Se status in the UK had been observed over the 1980s in longitudinal studies on same subjects

1728- SFN,    Broccoli sprouts: An exceptionally rich source of inducers of enzymes that protect against chemical carcinogens
- Review, Nor, NA
eff↑, 3-day-old sprouts of cultivars of certain crucifers including broccoli and cauliflower contain 10-100 times higher levels of glucoraphanin.All sprouts were grown with a 16-h light and 8-h dark photoperiod and a corresponding 25/20°C cycle for agar-gr
eff↓, The generally lower potencies of frozen broccoli samples may have been due to unfavorable storage conditions or to removal of glucosinolates during the blanching process

1727- SFN,    Glucoraphanin, sulforaphane and myrosinase activity in germinating broccoli sprouts as affected by growth temperature and plant organs
- Analysis, Nor, NA
eff↑, Sulforaphane formation was highest in cotyledon and lowest in root. Sprouts grown at 25 °C had higher glucoraphanin content
eff↓, Glucoraphanin content and sulforaphane formation declined with sprouts growth.

1455- SFN,    Sulforaphane Activates a lysosome-dependent transcriptional program to mitigate oxidative stress
- in-vitro, Cerv, HeLa - in-vitro, Nor, 1321N1
*ROS↓, SFN may trigger a self-defense cellular mechanism that can effectively mitigate oxidative stress commonly associated with many metabolic and age-related diseases. SFN treatment prevented CCCP-induced ROS increases in WT 1321N1 cells(normal)
*BioAv↑, Tissue concentrations of SFN can reach 3–30 μM upon broccoli consumption
LC3II↑, SFN (15 μM, 3–9 h) treatment markedly increased endogenous LC3-II levels in HeLa cells
LAMP1?, gradual (within hours) increases in the expression of LAMP1 proteins upon SFN (15 μM, 3–9 h) treatment in HeLa cells
TumAuto↑, SFN led to enhanced lysosomal and autophagic function.
TFEB↑, SFN (10–15 μM) treatment for 4 h induced nuclear translocation of endogenous TFEB in HeLa cells
ROS↑, SFN treatment for 2 h resulted in a mild increase of intracellular ROS. ROS mediate some effects of SFN
eff↓, NAC (5 mM), a commonly used membrane-permeable antioxidant compound [7], prevented SFN-induced increases in ROS

1482- SFN,    Sulforaphane induces apoptosis in T24 human urinary bladder cancer cells through a reactive oxygen species-mediated mitochondrial pathway: the involvement of endoplasmic reticulum stress and the Nrf2 signaling pathway
- in-vitro, Bladder, T24
tumCV↓,
Apoptosis↑,
Cyt‑c↑,
Bax:Bcl2↑, Bcl-2/Bax dysregulation
Casp9↑,
Casp3↑,
Casp8∅,
cl‑PARP↑,
ROS↑, sulforaphane triggered reactive oxygen species (ROS) generation
MMP↓,
eff↓, blockage of sulforaphane-induced loss of mitochondrial membrane potential and apoptosis, was strongly attenuated by the ROS scavenger N-acetyl-L-cysteine.
ER Stress↑,
p‑NRF2↑, accumulation of phosphorylated Nrf2 proteins in the nucleus
HO-1↑, induction of heme oxygenase-1 expression

1483- SFN,    Targeting p62 by sulforaphane promotes autolysosomal degradation of SLC7A11, inducing ferroptosis for osteosarcoma treatment
- in-vitro, OS, 143B - in-vitro, Nor, HEK293 - in-vivo, OS, NA
AntiCan↑, has shown potential anti-cancer effects with negligible toxicity
*toxicity∅, (liver, kidney, heart, spleen, and lung) showed no evidence of toxicity associated with SFN treatment
Ferroptosis↑, results demonstrate the dependency of downregulation of SLC7A11 in SFN-induced ferroptosis in OS cells
ROS↑, elevated ROS levels, lipid peroxidation, and GSH depletion
lipid-P↑,
GSH↓, which was dependent on decreased levels of SLC7A11
p62↑, enhanced p62/SLC7A11 protein-protein interaction, thereby promoting the lysosomal degradation of SLC7A11 and triggering ferroptosis
SLC12A5↓, SFN induces ferroptosis of OS cells through downregulation of SLC7A11
eff↓, ferroptosis inhibitors Fer-1 (ferrostatin-1), DFO (deferoxamine), and Lip-1 (liproxstatin-1) substantially rescued the cells from SFN-induced cell death
GPx4↓, SFN treatment markedly reduced the expression levels of ferroptosis markers GPX4 and SLC7A11 in OS cells
i-Iron↑, validated the intracellular Fe2+ accumulation by SFN
eff↓, SLC7A11 overexpression notably reversed SFN-induced changes in the ROS level, GSH level, and lipid peroxidation
MDA↑, SFN treatment reduced GSH levels and increased MDA production, indicating the induction of ferroptosis
TumVol↓,
TumW↓,
Ki-67↓, subcutaneous tumors revealed significantly lower expression levels of Ki67, SLC7A11, and GPX4, along with upregulated LC3B in the SFN-treated group
LC3B↑,
*Weight∅, no significant difference in body weight was observed between the control and SFN-treated groups

1484- SFN,    Sulforaphane’s Multifaceted Potential: From Neuroprotection to Anticancer Action
- Review, Var, NA - Review, AD, NA
neuroP↑, current evidence supporting the neuroprotective and anticancer effects of SFN
AntiCan↑,
NRF2↑, neuroprotective effects through the activation of the Nrf2 pathway
HDAC↓, histone deacetylase was inhibited after human subjects ingested 68 g of broccoli sprouts
eff↑, sensitize cancer cells to chemotherapy
*ROS↓, protecting neurons [14] and microglia [15] against oxidative stress
neuroP↑, neuroprotective effects in Alzheimer’s disease (AD)
HDAC↓, capacity as a histone deacetylase (HDAC) inhibitor
*toxicity∅, normal cells are relatively resistant to SFN-induced cell death
BioAv↑, SFN has good bioavailability; it can reach high intracellular and plasma concentrations
eff↓, However, it is important to consider that at lower doses, specifically 2.5 μM, SFN resulted in a slight increase in cell proliferation by 5.18–11.84% within a 6 to 48 h treatment window
cycD1↓, in breast cancer
CDK4↓, in breast cancer
p‑RB1↓, in breast cancer
Glycolysis↓, in prostate cancer
miR-30a-5p↑, ovarian cancer
TumCCA↑, gastric cancer
TumCG↓,
TumMeta↓,
eff↑, SFN emerged as a critical enhancer of ST’s efficacy by suppressing resistance in RCC cells, offering a potent approach to overcome ST monotherapy limitations.
ChemoSen↑, SFN may improve the effectiveness of chemotherapy by increasing cancer cell sensitivity to the drugs used to treat them
RadioS↑, SFN may help protect healthy cells and tissues from the harmful effects of radiation
CardioT↓, Several studies have demonstrated the protective role of SFN in cardiotoxicity
angioG↓, In colon cancers, SFN blocks cells’ progression and angiogenesis by inhibiting HIF-1α and VEGF expression
Hif1a↓,
VEGF↓,
*BioAv?, SFN is well absorbed in the intestine, with an absolute bioavailability of approximately 82%.
*Half-Life∅, In rats, after an oral dose of 50 μmol of SFN, the plasma concentration of SFN can peak at 20 μM at 4 h and decline with a half-life of about 2.2 h

1495- SFN,  doxoR,    Sulforaphane protection against the development of doxorubicin-induced chronic heart failure is associated with Nrf2 Upregulation
- in-vivo, Nor, NA
*CardioT↓, SFN significantly prevented DOX-induced progressive cardiac dysfunction between 2-6 weeks and prevented DOX-induced cardiac function deterioration.
*NRF2↑, SFN upregulated NF-E2-related factor 2 (Nrf2)
*eff↓, protective effect of SFN against DOX-induced fibrotic and inflammatory responses was abolished by Nrf2 silencing.
*ROS↓, prevented DOX-induced cardiac oxidative stress

1456- SFN,    Sulforaphane regulates cell proliferation and induces apoptotic cell death mediated by ROS-cell cycle arrest in pancreatic cancer cells
- in-vitro, PC, MIA PaCa-2 - in-vitro, PC, PANC1
tumCV↓,
TumCP↓,
cl‑PARP↑,
cl‑Casp3↑,
TumCCA↑, accumulation in the sub G1 phase
ROS↑, SFN caused a considerable increase in ROS in MIA PaCa-2 and PANC-1 cells as compared to the control group
MMP↓, SFN increased ROS level and γH2A.X expression while decreasing mitochondrial membrane potential (ΔΨm).
γH2AX↑,
eff↓, (NAC) was shown to reverse SFN-induced cytotoxicity and ROS level.
*toxicity↓, HUVECs, used as normal control cells, did not show significant inhibitory effects at SFN concentrations below 20 μM

1458- SFN,    Sulforaphane Impact on Reactive Oxygen Species (ROS) in Bladder Carcinoma
- Review, Bladder, NA
HDAC↓, SFN’s role as a natural HDAC-inhibitor is highly relevant
eff↓, SFN exerts stronger anti-proliferative effects on bladder cancer cell lines under hypoxia, compared to normoxic conditions
TumW↓, mice, SFN (52 mg/kg body weight) for 2 weeks reduced tumor weight by 42%
TumW↓, In another study a 63% inhibition was noted when tumor bearing mice were treated with SFN (12 mg/kg body weight) for 5 weeks
angioG↓,
*toxicity↓, In both investigations, the administration of SFN did not evoke apparent toxicity
GutMicro↝, SFN may protect against chemical-induced bladder cancer by normalizing the composition of gut microbiota and repairing pathophysiological destruction of the gut barrier,
AntiCan↑, A prospective study involving nearly 50,000 men indicated that high cruciferous vegetable consumption may reduce bladder cancer risk
ROS↑, Evidence shows that SFN upregulates the ROS level in T24 bladder cancer cells to induce apoptosis
MMP↓,
Cyt‑c↑,
Bax:Bcl2↑,
Casp3↑,
Casp9↑,
Casp8∅,
cl‑PARP↑,
TRAIL↑, ROS generation promotes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitivity
DR5↑,
eff↓, Blockade of ROS generation inhibited apoptotic activity and prevented Nrf2 activation in cells treated with SFN, pointing to a direct effect of ROS on apoptosis
NRF2↑, SFN potently inhibits carcinogenesis via activation of the Nrf2 pathway
ER Stress↑, endoplasmic reticulum stress evoked by SFN
COX2↓, downregulates COX-2 in T24 cells
EGFR↓, downregulation of both the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER2/neu
HER2/EBBR2↓,
ChemoSen↑, gemcitabine/cisplatin and SFN triggered pathway alterations in bladder cancer may open new therapeutic strategies, including a combined treatment regimen to cause additive effects.
NF-kB↓,
TumCCA?, cell cycle at the G2/M phase
p‑Akt↓,
p‑mTOR↓,
p70S6↓,
p19↑, p19 and p21, are elevated under SFN
P21↑,
CD44↓, CD44s expression correlates with induced intracellular levels of ROS in bladder cancer cells variants v3–v7 on bladder cancer cells following SFN exposure

1459- SFN,  Aur,    Auranofin Enhances Sulforaphane-Mediated Apoptosis in Hepatocellular Carcinoma Hep3B Cells through Inactivation of the PI3K/Akt Signaling Pathway
- in-vitro, Liver, Hep3B - in-vitro, Liver, HepG2
eff↑, sulforaphane significantly enhanced auranofin-induced apoptosis by inhibiting TrxR activity and cell proliferation compared to either single treatment
TumCCA↑, Sub-G1 cells
Apoptosis↑,
MMP↓,
BAX↑,
cl‑PARP↑,
Casp3↑,
Casp8↑,
Casp9↑,
ROS↑, combined treatment induced excessive generation of reactive oxygen species (ROS)
eff↓, treatment with N-acetyl-L-cysteine, a ROS scavenger, reduced combined treatment-induced ROS production and apoptosis.
PI3K↓,
Akt↓,
TrxR↓, treatment with either sulforaphane or auranofin alone at low concentrations weakly inhibit TrxR activity Combined treatment significantly reduced TrxR activity and cell viability
BAX↑,
Bcl-2∅,

1460- SFN,    High levels of EGFR prevent sulforaphane-induced reactive oxygen species-mediated apoptosis in non-small-cell lung cancer cells
- in-vitro, Lung, NA
ROS↑, Sulforaphane (SFN) has been shown to induce the production of reactive oxygen species (ROS) and inhibit epidermal growth factor receptor (EGFR)
EGFR↓,
eff↓, We present evidence that cells with high-level EGFR expression (CL1-5) are more resistant to SFN treatment than those with low-level expression (CL1-0)
TumCCA↑, S-phase
γH2AX↑,
DNAdam↑,
eff↓, Pretreatment with the antioxidant N-acetyl-L-cysteine prevented SFN-induced apoptosis in CL1-0 cells and production of γH2AX in both CL1-0 and CL1-5 cells.

1463- SFN,    Sulforaphane induces reactive oxygen species-mediated mitotic arrest and subsequent apoptosis in human bladder cancer 5637 cells
- in-vitro, Bladder, 5637
tumCV↓,
CycB↑, concomitant increased complex between cyclin B1 and Cdk1
p‑CDK1↑, of cyclin B1 and phosphorylation of Cdk1
Apoptosis↑,
Casp8↑,
Casp9↑,
Casp3↑,
cl‑PARP↑,
ROS↑, maximum level of ROS accumulation was observed 3h after sulforaphane treatment.
eff↓, ROS scavenger, N-acetyl-L-cysteine, notably attenuated sulforaphane-mediated apoptosis as well as mitotic arrest

1464- SFN,    d,l-Sulforaphane Induces ROS-Dependent Apoptosis in Human Gliomablastoma Cells by Inactivating STAT3 Signaling Pathway
- in-vitro, GBM, NA
Apoptosis↑,
Casp3↑,
BAX↑,
Bcl-2↓,
ROS↑, SFN treatment led to increase the intracellular reactive oxygen species (ROS) level in GBM cells
p‑STAT3↓,
JAK2↓,
eff↓, blockage of ROS production by using the ROS inhibitor N-acetyl-l-cysteine totally reversed SFN-mediated down-regulation of JAK2/Src-STAT3 signaling activation and the subsequent effects on apoptosis

1465- SFN,    TRAIL attenuates sulforaphane-mediated Nrf2 and sustains ROS generation, leading to apoptosis of TRAIL-resistant human bladder cancer cells
- NA, Bladder, NA
eff↑, Combined treatment with SFN and TRAIL (SFN/TRAIL) significantly induced apoptosis
Apoptosis↑,
Casp↑,
MMP↓,
BID↑,
DR5↑,
ROS↑, SFN increased both the generation of reactive oxygen species (ROS) and the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which is an anti-oxidant enzyme.
NRF2↑,
eff↑, Interestingly, TRAIL effectively suppressed SFN-mediated nuclear translocation of Nrf2, and the period of ROS generation was more extended compared to that of treatment with SFN alone.
eff↓, blockade of ROS generation inhibited apoptotic activity

1466- SFN,    Sulforaphane inhibits thyroid cancer cell growth and invasiveness through the reactive oxygen species-dependent pathway
- vitro+vivo, Thyroid, FTC-133
TumCP↓,
TumCCA↑, G2/M phase
Apoptosis↑,
TumCMig↓,
TumCI↓,
EMT↓,
Slug↓,
Twist↓,
MMP2↓,
MMP9↓,
TumCG↓,
p‑Akt↓,
P21↑,
ERK↑,
p38↑,
ROS↑, ROS was significantly induced in both FTC133 and K1 cells when cells were treated with 40 μM SFN for 4 h Several previous studies have shown that SFN induces ROS
*toxicity∅, we did not find significant effect of SFN on body weight and liver function of mice.
MMP↓,
eff↓, Like NAC, ASC treatment significantly attenuated anti-proliferative effect of SFN in these two cell lines

1467- SFN,    Sulforaphane generates reactive oxygen species leading to mitochondrial perturbation for apoptosis in human leukemia U937 cells
- in-vitro, AML, U937
Apoptosis↑,
ROS↑,
MMP↓, collapse of MMP
Casp3↑,
Bcl-2↓,
eff↓, quenching of ROS generation with antioxidant N-acetyl-L-cysteine conferred significant protection against sulforaphane-elicited ROS generation, disruption of the MMP, caspase-3 activation and apoptosis.

1480- SFN,    Sulforaphane Induces Cell Death Through G2/M Phase Arrest and Triggers Apoptosis in HCT 116 Human Colon Cancer Cells
- in-vitro, CRC, HCT116
tumCV↓,
TumCCA↑, G2/M phase arrest
Apoptosis↑,
cycA1↑,
CycB↑,
CDC25↓, Cdc 25C
CDK1↓,
ROS↑, SFN induced the generation of reactive oxygen species (ROS)
eff↓, Ca[Formula: see text] and decreased mitochondria membrane potential and increased caspase-8, -9 and -3 activities in HCT 116 cell
Cyt‑c↑,
AIF↑,
ER Stress↑,

1469- SFN,    Sulforaphane enhances the therapeutic potential of TRAIL in prostate cancer orthotopic model through regulation of apoptosis, metastasis, and angiogenesis
- in-vitro, Pca, PC3 - in-vitro, Pca, LNCaP - in-vivo, Pca, NA
eff↑, Sulforaphane enhanced the therapeutic potential of TRAIL in PC-3 cells and sensitized TRAIL-resistant LNCaP cells.
ROS↑,
MMP↓,
Casp3↑,
Casp9↑,
DR4↑,
DR5↑,
BAX↑,
Bak↑,
BIM↑,
NOXA↑,
Bcl-2↓,
Bcl-xL↓,
Mcl-1↓,
eff↓, quenching of ROS generation with antioxidant N-acetyl-L-cysteine conferred significant protection against sulforaphane-induced ROS generation, mitochondrial membrane potential disruption, caspase-3 activation, and apoptosis.
TumCG↓,
TumCP↓,
eff↑, enhanced the antitumor activity of TRAIL.
NF-kB↓,
PI3K↓,
Akt↓,
MEK↓,
ERK↓,
angioG↓, combination of sulforaphane and TRAIL was more effective in inhibiting markers of angiogenesis and metastasis and activating FOXO3a transcription factor than single agent alone.
FOXO3↑,

1470- SFN,  Rad,    Sulforaphane induces ROS mediated induction of NKG2D ligands in human cancer cell lines and enhances susceptibility to NK cell mediated lysis
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231 - in-vitro, Lung, A549 - in-vitro, lymphoma, U937
eff↓, NK cell mediated killing was abrogated by N-acetyl cysteine in A549 and MDA-MB-231 cells suggesting a ROS mediated mechanism.
ROS↑,
NKG2D↑, ability to up-regulate natural killer group 2, member D (NKG2D) ligands and modulate the susceptibility of tumor cells to natural killer (NK) cell-mediated killing.

1471- SFN,    ROS-mediated activation of AMPK plays a critical role in sulforaphane-induced apoptosis and mitotic arrest in AGS human gastric cancer cells
- in-vitro, GC, AGS
TumCP↓,
Apoptosis↑,
TumCCA↑, G2/M phase
CycB↑,
P21↑,
p‑H3↑,
p‑AMPK↑,
eff↓, compound C, an AMPK inhibitor, significantly blocked sulforaphane-induced apoptosis
MMP↓,
Cyt‑c↑,
ROS↑, sulforaphane provoked the generation of intracellular ROS
eff↓, sulforaphane provoked the generation of intracellular ROS; especially when ROS production was blocked by antioxidant N-acetylcysteine, both AMPK activation and growth inhibition by sulforaphane were completely abolished

1474- SFN,    Sulforaphane induces p53‑deficient SW480 cell apoptosis via the ROS‑MAPK signaling pathway
- in-vitro, Colon, SW480
TumCG↓,
Apoptosis↑,
MMP↓,
Bax:Bcl2↑,
Casp3↑,
Casp7↑,
Casp9↑,
ROS↑, increase in the generation of reactive oxygen species (ROS)
e-ERK↑, activation of extracellular signal‑regulated kinases (Erk)
p38↑,
P53∅,
eff↓, specific inhibitors for ROS, phosphorylated (p)‑Erk and p‑p38, completely or partially attenuated the SFN‑induced reduction in SW480 cell viability
ChemoSen↑, even at the lowest concentrations (5 µM), SFN increased the sensitivity of p53‑proficient HCT‑116 cells to cisplatin

1476- SFN,  PDT,    Enhancement of cytotoxic effect on human head and neck cancer cells by combination of photodynamic therapy and sulforaphane
- in-vitro, HNSCC, NA
eff↑, Cell viability was decreased significantly by combination treatment
tumCV↓,
ROS↑, ROS generation was also higher in combination treatment
eff↓, In combination treatment group, apoptosis and necrosis were decreased by administration of sodium azide (SA) which is scavenger of ROS.
Casp↑,

1508- SFN,    Nrf2 targeting by sulforaphane: A potential therapy for cancer treatment
- Review, Var, NA
*BioAv↑, RAW: higher amounts were detected when broccoli were eaten raw (bioavailability equal to 37%), compared to the cooked broccoli (bioavailability 3.4%)
HDAC↓, Sulforaphane is able to down-regulate HDAC activity and induce histone hyper-acetylation in tumor cell
TumCCA↓, Sulforaphane induces cell cycle arrest in G1, S and G2/M phases,
eff↓, in leukemia stem cells, sulforaphane potentiates imatinib effect through inhibition of the Wnt/β-catenin functions
Wnt↓,
β-catenin/ZEB1↓,
Casp12?, inducing caspases activation
Bcl-2↓,
cl‑PARP↑,
Bax:Bcl2↑, unbalancing the ratio Bax/Bcl-2
IAP1↓, down-regulating IAP family proteins
Casp3↑,
Casp9↑,
Telomerase↓, In Hep3B cells, sulforaphane reduces telomerase activity
hTERT↓, inhibition of hTERT expression;
ROS?, increment of ROS, induced by this compound, is essential for the downregulation of transcription and of post-translational modification of hTERT in suppression of telomerase activity
DNMTs↓, (2.5 - 10 μM) represses hTERT by impacting epigenetic pathways, in particular through decreased DNA methyltransferases activity (DNMTs)
angioG↓, inhibit tumor development through regulation of angiogenesis
VEGF↓,
Hif1a↓,
cMYB↓,
MMP1↓, inhibition of migration and invasion activities induced by sulforaphane in oral carcinoma cell lines has been associated to the inhibition of MMP-1 and MMP-2
MMP2↓,
MMP9↓,
ERK↑, inhibits invasion by activating ERK1/2, with consequent upregulation of E-cadherin (an invasion inhibitor)
E-cadherin↑,
CD44↓, downregulation of CD44v6 and MMP-2 (invasion promoters)
MMP2↓,
eff↑, ombination of sulforaphane and quercetin synergistically reduces the proliferation and migration of melanoma (B16F10) cells
IL2↑, induces upregulation of IL-2 and IFN-γ
IFN-γ↑,
IL1β↓, downregulation of IL-1beta, IL-6, TNF-α, and GM-CSF
IL6↓,
TNF-α↓,
NF-kB↓, sulforaphane inhibits the phorbol ester induction of NF-κB, inhibiting two pathways, ERK1/2 and NF-κB
ERK↓,
NRF2↑, At molecular level, sulforaphane modulates cellular homeostasis via the activation of the transcription factor Nrf2.
RadioS↑, sulforaphane could be used as a radio-sensitizing agent in prostate cancer if clinical trials will confirm the pre-clinical results.
ChemoSideEff↓, chemopreventive effects of sulforaphane

3298- SIL,    Silibinin, a natural flavonoid, induces autophagy via ROS-dependent mitochondrial dysfunction and loss of ATP involving BNIP3 in human MCF7 breast cancer cells
- in-vitro, BC, MCF-7
LC3II↑, silibinin triggered the conversion of light chain 3 (LC3)-I to LC3-II, promoted the upregulation of Atg12-Atg5 formation, increased Beclin-1 expression, and decreased the Bcl-2 level.
Beclin-1↑,
Bcl-2↓,
ROS↑, Moreover, we noted elevated reactive oxygen species (ROS) generation, concomitant with the dissipation of mitochondrial transmembrane potential (ΔΨm) and a drastic decline in ATP levels following silibinin treatment,
MMP↓,
ATP↓,
eff↓, which were effectively prevented by the antioxidants, N-acetylcysteine and ascorbic acid
BNIP3?, silibinin upregulated BNIP3 protein and transcript levels
TumAuto↑, uggesting that the MCF7 cells were more sensitive to silibinin-induced autophagic cell death under the starvation condition.
eff↑, more sensitive to silibinin-induced autophagic cell death under the starvation condition.

2217- SK,    Shikonin Inhibits Endoplasmic Reticulum Stress-Induced Apoptosis to Attenuate Renal Ischemia/Reperfusion Injury by Activating the Sirt1/Nrf2/HO-1 Pathway
- in-vivo, Nor, NA - in-vitro, Nor, HK-2
*ER Stress↓, shikonin alleviated ER stress-induced apoptosis in I/R mice
*SIRT1↑, shikonin activated Sirt1/Nrf2/HO-1 signaling post-I/R
*NRF2↑,
*HO-1↑,
*eff↓, inhibition of Sirt1 limited shikonin-mediated protection against ER stress-stimulated apoptosis in both animal and cellular models.
*RenoP↑, Shikonin pretreatment alleviates renal I/R injury through activating Sirt1/Nrf2/HO-1 signaling to inhibit ER stress-mediated apoptosis.
*GRP78/BiP↓, The current study revealed that shikonin significantly downregulated GRP78, CHOP, caspase-12, Bax, and cleaved caspase-3 proteins levels in renal tissues of I/R mice and H/R-challenged HK-2 cells
*CHOP↓,
*Casp12↓,
*BAX↓,
*cl‑Casp3↓,

2230- SK,    Shikonin induces ROS-based mitochondria-mediated apoptosis in colon cancer
- in-vitro, CRC, HCT116 - in-vivo, NA, NA
TumCG↓, shikonin suppressed the growth of colon cancer cells in a dose-dependent manner in vitro and in vivo
Bcl-2↓, Shikonin induced mitochondria-mediated apoptosis, which was regulated by Bcl-2 family proteins.
ROS↑, found that shikonin dose-dependently increased the generation of intracellular ROS in colon cancer cells
Bcl-xL↓, generation of ROS, down-regulated expression of Bcl-2 and Bcl-xL, depolarization of the mitochondrial membrane potential and activation of the caspase cascade
MMP↓,
Casp↑,
selectivity↑, shikonin presented minimal toxicity to non-neoplastic colon cells and no liver injury in xenograft models
cycD1↓, Cyclin D expression was decreased with shikonin treatment
TumCCA↑, induced cell growth inhibition by the induction G1 cell cycle arrest.
eff↓, NAC or GSH could block the shikonin-dependent burst of intracellular ROS

2229- SK,    Shikonin induces apoptosis and prosurvival autophagy in human melanoma A375 cells via ROS-mediated ER stress and p38 pathways
- in-vitro, Melanoma, A375
Apoptosis↑, Shikonin induces apoptosis and autophagy in A375 cells and inhibits their proliferation
TumAuto↑,
TumCP↓,
TumCCA↑, Shikonin caused G2/M phase arrest through upregulation of p21 and downregulation of cyclin B1
P21↑,
cycD1↓,
ER Stress↑, Shikonin significantly triggered ER stress-mediated apoptosis by upregulating the expression of p-eIF2α, CHOP, and cleaved caspase-3.
p‑eIF2α↑,
CHOP↑,
cl‑Casp3↑,
p38↑, induced protective autophagy by activating the p38 pathway, followed by an increase in the levels of p-p38, LC3B-II, and Beclin 1
LC3B-II↑,
Beclin-1↑,
ROS↑, Shikonin increased the production of reactive oxygen species
eff↓, NAC treatment significantly decreased the expression of p-p38, LC3B-II, and Beclin 1.

2228- SK,    Shikonin induced Apoptosis Mediated by Endoplasmic Reticulum Stress in Colorectal Cancer Cells
- in-vitro, CRC, HCT116 - in-vitro, CRC, HCT15 - in-vivo, NA, NA
Apoptosis↑, shikonin induced cell apoptosis by down-regulating BCL-2 and activating caspase-3/9 and the cleavage of PARP.
Bcl-2↓,
Casp3↑,
Casp9↑,
cl‑PARP↑,
GRP78/BiP↑, The expression of BiP and the PERK/elF2α/ATF4/CHOP and IRE1α /JNK signaling pathways were upregulated after shikonin treatment.
PERK↑,
eIF2α↑,
ATF4↑,
CHOP↑,
JNK↑,
eff↓, pre-treatment with N-acetyl cysteine significantly reduced the cytotoxicity of shikonin
ER Stress↑, Shikonin induced endoplasmic reticulum stress
ROS↑, Shikonin induced reactive oxygen species-mediated ER stress
TumCG↓, Shikonin suppressed the growth of colorectal cancer cells in vivo

2227- SK,    Shikonin induces mitochondria-mediated apoptosis and enhances chemotherapeutic sensitivity of gastric cancer through reactive oxygen species
- in-vitro, GC, BGC-823 - in-vitro, GC, SGC-7901 - in-vitro, Nor, GES-1
selectivity↑, In vitro, SHK suppresses proliferation and triggers cell death of gastric cancer cells but leads minor damage to gastric epithelial cells.
TumCP↓,
TumCD↑,
ROS↑, SHK induces the generation of intracellular reactive oxygen species (ROS), depolarizes the mitochondrial membrane potential (MMP) and ultimately triggers mitochondria-mediated apoptosis.
MMP↓,
Casp↑, SHK induces apoptosis of gastric cancer cells not only in a caspase-dependent manner which releases Cytochrome C and triggers the caspase cascade
Cyt‑c↑,
Endon↑, nuclear translocation of AIF and Endonuclease G
AIF↑,
eff↓, NAC and GSH significantly inhibited SHK-induced death
ChemoSen↑, SHK enhances chemotherapeutic sensitivity of 5-fluorouracil and oxaliplatin
TumCCA↑, SHK caused S-phase cell cycle arrest in SGC-7901 and BGC-823 gastric cancer cells
GSH/GSSG↓, We found that the GSH/GSSG ratio was significantly decreased when treated with SHK.
lipid-P↑, SHK increases lipid peroxidation and induces apoptosis in vivo

2226- SK,    Shikonin, a Chinese plant-derived naphthoquinone, induces apoptosis in hepatocellular carcinoma cells through reactive oxygen species: A potential new treatment for hepatocellular carcinoma
- in-vitro, HCC, HUH7 - in-vitro, HCC, Bel-7402
selectivity↑, shikonin induced apoptosis of Huh7 and BEL7402 but not nontumorigenic cells.
ROS↑, ROS generation was detected
eff↓, ROS scavengers completely inhibited shikonin-induced apoptosis, indicating that ROS play an essential role
Akt↓, downregulation of Akt and RIP1/NF-κB activity was found to be involved in shikonin-induced apoptosis
RIP1↓,
NF-kB↓,

2469- SK,    Shikonin induces the apoptosis and pyroptosis of EGFR-T790M-mutant drug-resistant non-small cell lung cancer cells via the degradation of cyclooxygenase-2
- in-vitro, Lung, H1975
Apoptosis↑, Shikonin induced cell apoptosis and pyroptosis by triggering the activation of the caspase cascade and cleavage of poly (ADP-ribose) polymerase and gasdermin E by elevating intracellular ROS levels
Pyro↑,
Casp↑,
cl‑PARP↑,
GSDME↑,
ROS↑,
COX2↓, shikonin induced the degradation of COX-2 via the proteasome pathway, thereby decreasing COX-2 protein level and enzymatic activity and subsequently inhibiting the downstream PDK1/Akt and Erk1/2 signaling pathways through the induction of ROS produc
PDK1↓,
Akt↓,
ERK↓,
eff↓, Notably, COX-2 overexpression attenuated shikonin-induced apoptosis and pyroptosis
eff↓, NAC pre-treatment inhibited the shikonin-induced activation of the caspase cascade (caspase-8/9/3) and cleavage of PARP and GSDME in H1975 cells
eff↑, Celecoxib augmented the cytotoxic effects of shikonin by promoting the apoptosis and pyroptosis of H1975 cells

3047- SK,    Shikonin suppresses colon cancer cell growth and exerts synergistic effects by regulating ADAM17 and the IL-6/STAT3 signaling pathway
- in-vitro, CRC, HCT116 - in-vitro, CRC, SW48
TumCG↓, SKN inhibited colon cancer cell growth, suppressed both constitutive and IL-6-induced STAT3 phosphorylation, and downregulated the expression of ADAM17
p‑STAT3↓,
ADAM17↓,
Apoptosis↑, SKN promoted cell apoptosis, as evidenced by increased expression levels of cleaved caspase-3 and cleaved PARP in both cell lines
Casp3↑,
cl‑PARP↑,
cycD1↓, SKN decreased the expression of cyclin D1 and cyclin E1, thus suggesting the disruption of the cell cycle and the suppression of cell growth
cycE↓,
TumCCA↑,
JAK1?, The inhibitory effects of SKN on the phosphorylation of both JAK1 and JAK2 in the two cell lines were also observed
p‑JAK1↓,
p‑JAK2↓,
p‑eIF2α↑, phosphorylation levels of eIF2α were enhanced by SKN (20 µM) in the HCT116 and SW480 colon cancer cells
eff↓, NAC decreased SKN-induced p-eIF2α expression and reversed the SKN-mediated downregulation of ADAM17 protein expression
ROS↑, suppressed the expression of ADAM17 mediated by ROS-associated p-eIF2α expression in the HCT116 and SW480 colon cancer cells
IL6↓, demonstrated that the antitumor effects of SKN on colon cancer cells were associated with its inhibition of the IL-6/STAT3 signaling pathway.

1344- SK,    Novel multiple apoptotic mechanism of shikonin in human glioma cells
- in-vitro, GBM, U87MG - in-vitro, GBM, Hs683 - in-vitro, GBM, M059K
ROS↑,
GSH↓,
MMP↓,
P53↑, upregulation of p53,
cl‑PARP↑,
Catalase↓,
SOD1↑,
Bcl-2↓,
BAX↑,
eff↓, Pretreatment with NAC, PFT-α, or cyclosporin A causes the recovery of shikonin-induced apoptosis.

2010- SK,    Shikonin inhibits gefitinib-resistant non-small cell lung cancer by inhibiting TrxR and activating the EGFR proteasomal degradation pathway
- in-vitro, Lung, H1975 - in-vitro, Lung, H1650 - in-vitro, Nor, CCD19
EGFR↓, Shikonin is a potent inhibitor of EGFR
selectivity↑, Shikonin exhibited selective cytotoxicity among two NSCLC cell lines (H1975 and H1650) and one normal lung fibroblast cell line (CCD-19LU).
Casp↑, Shikonin significantly increased the activity of caspases and poly (ADP-ribosyl) polymerase (PARP), which are indicators of apoptosis
PARP↑,
Apoptosis↑,
ROS↑, intensity of ROS by greater than 10-fold
eff↓, NAC, an inhibitor of ROS, completely blocked apoptosis, caspase and PARP activation induced by Shikonin.
selectivity↑, the IC50 value of Shikonin in CCD19 (normal cells) is approximately 4-fold higher than that of HCC827, H1650 and H1975.

2008- SK,  Cisplatin,    Enhancement of cisplatin-induced colon cancer cells apoptosis by shikonin, a natural inducer of ROS in vitro and in vivo
- in-vitro, CRC, HCT116 - in-vivo, NA, NA
ChemoSen↑, combination of shikonin and cisplatin exhibited synergistic anticancer efficacy
selectivity↑, and achieved greater selectivity between cancer cells and normal cells.
i-ROS↑, By inducing intracellular oxidative stress, shikonin potentiated cisplatin-induced DNA damage, followed by increased activation of mitochondrial pathway.
DNAdam↑,
MMP↓,
TumCCA↑, induction of G2/M cell cycle arrest
eff↓, NAC and GSH were used in our experiment. The MTT results revealed that scavenging of ROS fully attenuated combined treatment-induced cell growth inhibition against HCT116 cell
*toxicity↓, combined treatment showed less cytotoxicity toward NCM460 normal human colon mucosal epithelial cells

2188- SK,    Molecular mechanism of shikonin inhibiting tumor growth and potential application in cancer treatment
- Review, Var, NA
ROS↑, their induction of reactive oxygen species production, inhibition of EGFR and PI3K/AKT signaling pathway activation, inhibition of angiogenesis and induction of apoptosis and necroptosis
EGFR↓,
PI3K↓,
Akt↓,
angioG↓,
Apoptosis↑,
Necroptosis↑,
GSH↓, leading to the increased consumption of reduced glutathione (GSH) and increased Ca2+ concentration in the cells and destroying the mitochondrial membrane potential.
Ca+2↓,
MMP↓,
ERK↓, 24 h of treatment with shikonin, ERK 1/2 and AKT activities were significantly inhibited, and p38 activity was upregulated, which ultimately led to pro-caspase-3 cleavage and triggered the apoptosis of GC cells.
p38↑,
proCasp3↑,
eff↓, pretreated with the ROS scavengers NAC and GSH before treatment with shikonin, the production of ROS was significantly inhibited, the cytotoxicity of shikonin was attenuated
VEGF↓, shikonin can inhibit the expression of VEGF
FOXO3↑, Activated FOXO3a/EGR1/SIRT1 signaling
EGR1↑,
SIRT1↑,
RIP1↑, Upregulation of RIP1 and RIP3
RIP3↑,
BioAv↓, limitations caused by its poor water solubility, it has a short half-life and nonselective biological distribution
NF-kB↓, Shikonin can also prevent the activation of NF-κB by AKT and then downregulate the expression of Bcl-xl,
Half-Life↓, due to the limitations caused by its poor water solubility, it has a short half-life and nonselective biological distribution.

2186- SK,    Shikonin differentially regulates glucose metabolism via PKM2 and HIF1α to overcome apoptosis in a refractory HCC cell line
- in-vitro, HCC, HepG2 - in-vitro, HCC, HCCLM3
Glycolysis↓, shikonin treatment has been reported to inhibit glycolysis by suppressing the activity of pyruvate kinase M2 (PKM2) and to induce apoptosis by increasing reactive oxygen species (ROS) production.
PKM2↓,
Apoptosis↑,
ROS↑,
OXPHOS⇅, Shikonin up-regulated mitochondrial biogenesis to increase mitochondrial oxidative phosphorylation in HepG2 cells, but displayed the opposite trend in HCCLM3 cells.
eff↓, insensitivity of HCCLM3 cells to shikonin treatment.

2213- SK,    Shikonin attenuates cerebral ischemia/reperfusion injury via inhibiting NOD2/RIP2/NF-κB-mediated microglia polarization and neuroinflammation
- in-vivo, Stroke, NA
*neuroP↑, Shikonin treatment significantly reduced brain infarction volume and improved neurological function in MCAO/R rats.
*Inflam↓, Shikonin treatment significantly reduced microglial proinflammatory phenotype and levels of proinflammatory markers (inducible-NO synthase (iNOS), tumor necrosis factor-alpha (TNF-α),
*iNOS↓,
*TNF-α↓,
*IL1β↓, interleukin-1 beta (IL-1β), and IL-6), increased microglial anti-inflammatory phenotype and levels of anti-inflammatory markers (Arginase-1 (Arg1), transforming growth factor-beta (TGF-β), and IL-10),
*IL6↓,
*ARG↑,
*TGF-β↑,
*IL10↑,
*NF-kB↓, reversed the expression of Nucleotide-binding oligomerization domain 2 (NOD2) and phosphorylation receptor interacting protein 2 (p-RIP2), and suppressed nuclear factor kappa-B (NF-κB) signaling activation in the ischemic penumbra regions.
*eff↓, Furthermore, overexpression of NOD2 markedly attenuated the neuroprotective effects of Shikonin treatment in MCAO/R rats.

2215- SK,  doxoR,    Shikonin alleviates doxorubicin-induced cardiotoxicity via Mst1/Nrf2 pathway in mice
- in-vivo, Nor, NA
*cardioP↑, Mice receiving shikonin showed reduced cardiac injury response and enhanced cardiac function after DOX administration
*ROS↓, Shikonin significantly attenuated DOX-induced oxidative damage, inflammation accumulation and cardiomyocyte apoptosis.
*Inflam↓,
*Mst1↓, Shikonin protects against DOX-induced cardiac injury by inhibiting Mammalian sterile 20-like kinase 1 (Mst1) and oxidative stress and activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway.
*NRF2↑,
*eff↓, Nrf2 knockdown counteracted the protective effects of shikonin on cardiac injury and dysfunction caused by DOX in mice
*antiOx↑, Previous studies have shown that shikonin possesses direct and indirect antioxidant properties, as evidenced by its ability to restore SOD expression and GSH levels, as well as block oxidative stress
*SOD↑,
*GSH↑,
*TNF-α↓, shikonin decreased the elevlated cardiac TNF-α induced by DOX
BAX↓, Shikonin attenuated DOX-induced upregulation of Bax and the down-regulation of Bcl-2
Bcl-2↑,

346- SNP,  RSQ,    Investigating Silver Nanoparticles and Resiquimod as a Local Melanoma Treatment
- in-vivo, Melanoma, SK-MEL-28 - in-vivo, Melanoma, WM35
ROS↑,
Ca+2↝, disrupt mitochondrial homeostasis of Ca2+
Casp3↑, x2-4
Casp8↑, x2-4
Casp9↑, x4-14
CD4+↑,
CD8+↑,
tumCV↓,
eff↓, NAC, an ROS scavenger, could efficiently protect B16.F10 cells from the cytotoxic effects of Ag+ even when exposed to high concentrations of Ag+ (250 μg/ml)
*toxicity↓, non-toxic in mice as evidenced by: 1) no significant change in weights during the study period and 2) no significant increases in the levels of liver enzymes, (ALP), (AST), and ALT

357- SNP,    Hypoxia-mediated autophagic flux inhibits silver nanoparticle-triggered apoptosis in human lung cancer cells
- in-vitro, Lung, A549 - in-vitro, Lung, L132
mtDam↑,
ROS↑,
Hif1a↑, HIF-1α expression was upregulated after AgNPs treatment under both hypoxic and normoxic conditions HIF-1α knockdown enhances hypoxia induced decrease in cell viability
LC3s↑,
p62↑,
eff↓, Hypoxia decreases the effects of anticancer drugs in solid tumor cells through the regulation of HIF-1α

2287- SNP,    Silver nanoparticles induce endothelial cytotoxicity through ROS-mediated mitochondria-lysosome damage and autophagy perturbation: The protective role of N-acetylcysteine
- in-vitro, Nor, HUVECs
*TumCP↓, AgNPs affects the morphology and function of endothelial cells which manifests as decreased cell proliferation, migration, and angiogenesis ability
*ROS↑, AgNPs can induce excessive cellular production of reactive oxygen species (ROS), leading to damage to cellular sub-organs such as mitochondria and lysosomes
*eff↓, treatment with ROS scavenger-NAC can effectively suppress AgNP-induced endothelial damage.
*MDA↑, exposure to AgNPs increased MDA levels and decreased GSH levels.
*GSH↓,
*MMP↓, significantly reduced both MMP and ATP levels (Fig. 7) in HUVECs,
*ATP↓,
*LC3II↑, expression levels of LC3-II and p62 were significantly increase
*p62↑,
*Bcl-2↓, the anti-apoptotic protein expression level of Bcl-2 in HUVECs decreased, while the pro-apoptotic protein expression levels of Bax and Caspase-3 increased significantly.
*BAX↑,
*Casp3↑,

1906- SNP,  GoldNP,  Cu,    Current Progresses in Metal-based Anticancer Complexes as Mammalian TrxR Inhibitors
- Review, Var, NA
TrxR↓, 183(Au) was able to decrease TrxR activity by 50% at 4.20 nM
eff↓, IC 50 value calculated for 184(Ag) was 10.30 nM
eff↓, Conversely, 185(Cu) was found to be much less effective in inhibiting TrxR activity, with an IC 50 value of 89.50 nM

1907- SNP,  GoldNP,  Cu,    In vitro antitumour activity of water soluble Cu(I), Ag(I) and Au(I) complexes supported by hydrophilic alkyl phosphine ligands
- in-vitro, Lung, A549 - in-vitro, BC, MCF-7 - in-vitro, Melanoma, A375 - in-vitro, Colon, HCT15 - in-vitro, Cerv, HeLa
TrxR↓, In particular, [Au(PTA)4]PF6 was able to decrease by 50% TrxR activity at 4.2 nM
eff↓, C 50 value calculated for [Ag(PTA) 4]PF6 was 10.3 nM.
eff↓, Conversely, [Cu(PTA)4]PF6 was found to be much less effective in inhibiting this cytosolic selenoenzyme, with an IC50 value of 89.5 nM, roughly from 9 to 21 times higher than those calculated for silver and gold derivatives,
other∅, To the best of our knowledge, this is the first example of a phosphino silver complex acting as TrxR inhibitor.

3403- TQ,    A multiple endpoint approach reveals potential in vitro anticancer properties of thymoquinone in human renal carcinoma cells
- in-vitro, RCC, 786-O
tumCV↓, TQ treatment clearly decreased cell viability in a concentration- and time-dependent manner.
ROS↑, TQ concentrations from 1 to 20 uM moderately increased ROS levels in approximately 20-30% comparing to control cells
TumCCA↑, an increase in the sub-G1 population was observed, especially at 30 μM,
eff↓, The co-treatment with GSH increases the cell viability of TQ-exposed cells
TumCI↓, As depicted in Fig. 8 (A-B), the % of invasion of 786-O cells treated with TQ (1 uM, 10 h) significantly decreased to 75.2% of controls

3412- TQ,    Thymoquinone induces oxidative stress-mediated apoptosis through downregulation of Jak2/STAT3 signaling pathway in human melanoma cells
- in-vitro, Melanoma, SK-MEL-28 - in-vivo, NA, NA
Apoptosis↑, Q treatment induced apoptosis in SK-MEL-28 cells
JAK2↓, Interestingly, constitutive phosphorylation of Janus kinase 2 (Jak2) and signal transducer and activator of transcription 3 (STAT3) was markedly decreased following TQ treatment
STAT3↓,
cycD1↓, TQ treatment downregulated STAT3-dependent genes including cyclin D1, D2, and D3 and survivin
survivin↓,
ROS↑, TQ increased the levels of reactive oxygen species (ROS)
eff↓, , whereas pretreatment with N-acetyl cysteine (NAC), a ROS scavenger, prevented the suppressive effect of TQ on Jak2/STAT3 activation and protected SK-MEL-28 cells from TQ-induced apoptosis.

3414- TQ,    Thymoquinone induces apoptosis through inhibition of JAK2/STAT3 signaling via production of ROS in human renal cancer Caki cells
- in-vitro, RCC, Caki-1
tumCV↓, TQ significantly reduced the cell viability and induced apoptosis in Caki cells as evidenced by the induction of p53 and Bax, release of cytochrome c, cleavage of caspase-9, and -3 and PARP and the inhibition of Bcl-2 and Bcl-xl expression.
Apoptosis↑,
P53↑,
BAX↑,
Cyt‑c↑,
cl‑Casp9↑,
cl‑Casp3↑,
cl‑PARP↑,
Bcl-2↓,
Bcl-xL↓,
p‑STAT3↓, TQ inhibited the constitutive phosphorylation of signal transducer and activator of transcription-3 (STAT3) in Caki cells by blocking the phosphorylation of upstream Janus-activated kinase-2 (JAK2) kinases.
p‑JAK2↓,
STAT3↓, TQ attenuated the expression of STAT3 target gene products, such as survivin, cyclin D1, and D2.
survivin↓,
cycD1↓,
ROS↑, Treatment with TQ generated ROS in these renal cancer cells.
eff↓, Pretreatment of cells with ROS scavenger N-acetyl cysteine (NAC) abrogated the inhibitory effect of TQ on the JAK2/STAT3 signaling and rescued cells from TQ-induced apoptosis

1934- TQ,    Studies on molecular mechanisms of growth inhibitory effects of thymoquinone against prostate cancer cells: role of reactive oxygen species
- in-vitro, Pca, PC3 - in-vitro, Pca, C4-2B
ROS↑, A dose-dependent increase in ROS generation was clearly evident at this time point. Almost a 3.25-fold increase in ROS levels were observed with 75 and 100 umol/L of TQ in both PC-3 and C4-2B cells.
GSH↓, GSH levels were significantly decreased by 50 and 100 umol/L TQ, showing 35% and 65% reductions in GSH levels
eff↓, Pretreatment with NAC protected PC-3 and C4-2B cells against TQ-induced ROS generation and growth inhibition

2129- TQ,  doxoR,    Thymoquinone up-regulates PTEN expression and induces apoptosis in doxorubicin-resistant human breast cancer cells
- in-vitro, BC, MCF-7
ChemoSen↑, TQ greatly inhibits doxorubicin-resistant human breast cancer MCF-7/DOX cell proliferation
PTEN↑, TQ treatment increased cellular levels of PTEN proteins
p‑Akt↓, resulting in a substantial decrease of phosphorylated Akt, a known regulator of cell survival.
TumCCA↑, TQ arrested MCF-7/DOX cells at G2/M phase and increased cellular levels of p53 and p21 proteins.
P53↑,
P21↑,
Apoptosis↑, TQ-induced apoptosis was associated with disrupted mitochondrial membrane potential and activation of caspases and PARP cleavage in MCF-7/DOX cells.
MMP↓,
Casp↑,
cl‑PARP↑,
Bax:Bcl2↑, TQ treatment increased Bax/Bcl2 ratio via up-regulating Bax and down-regulating Bcl2 proteins.
eff↓, PTEN silencing by target specific siRNA enabled the suppression of TQ-induced apoptosis resulting in increased cell survival.
DNAdam↓, TQ treatment arrests MCF-7/DOX Cells in G2/M phase and induces DNA damage
p‑γH2AX↑, time-dependent increase in the phosphorylation of H2AX was observed following TQ treatment
ROS↑, DNA damage caused by TQ induced reactive species and oxidative stress.

2135- TQ,    Thymoquinone induces heme oxygenase-1 expression in HaCaT cells via Nrf2/ARE activation: Akt and AMPKα as upstream targets
- in-vitro, Nor, HaCaT
*HO-1↑, TQ induced the expression of HO-1 in HaCaT/ Cells treated with TQ (1, 5, 10, 20 lM) for 6 h induced the expression of HO-1 protein. maximal induction observed until 12 h and then returned to basal level time thereafter
*NRF2↑, Treatment with TQ increased the localization of nuclear factor (NF)-erythroid2-(E2)-related factor-2 (Nrf2) in the nucleus and elevated the antioxidant response element (ARE)-reporter gene activity.
*e-ERK↑, TQ induced the phosphorylation of extracellular signal-regulated kinase (ERK), Akt and cyclic AMP-activated protein kinase-α (AMPKα).
*e-Akt↑,
*AMPKα↑,
*ROS⇅, Treatment of HaCaT cells with TQ resulted in a concentration-dependent increase in the intracellular accumulation of ROS (most occurs at 20uM concentration -see figure 5A) (later it drops the ROS)
*eff↓, pretreatment with N-acetyl cysteine (NAC) abrogated TQ-induced ROS accumulation, Akt and AMPKα activation, Nrf2 nuclear localization, the ARE-luciferase activity, and HO-1 expression in HaCaT cells
*tumCV∅, does not change much 1-20uM of TQ (normal cells) see figure 1A

2121- TQ,    Thymoquinone Inhibits Tumor Growth and Induces Apoptosis in a Breast Cancer Xenograft Mouse Model: The Role of p38 MAPK and ROS
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-231
p‑p38↑, Here, we show that TQ induced p38 phosphorylation and ROS production in breast cancer cells
ROS↑,
TumCP↓, These inductions were found to be responsible for TQ’s anti-proliferative and pro-apoptotic effect
eff↑, TQ treatment was found to suppress the tumor growth and this effect was further enhanced by combination with doxorubicin
XIAP↓, TQ also inhibited the protein expression of anti-apoptotic genes, such as XIAP, survivin, Bcl-xL and Bcl-2, in breast cancer cells and breast tumor xenograf
survivin↓,
Bcl-xL↓,
Bcl-2↓,
Ki-67↓, Reduced Ki67 and increased TUNEL staining were observed in TQ-treated tumors
*Catalase↑, TQ was also found to increase the level of catalase, superoxide dismutase and glutathione in mouse liver tissues.
*SOD↑,
*GSH↑,
hepatoP↑,
p‑MAPK↑, TQ significantly up-regulated the phosphorylation of various MAPKs in MCF-7 cells
JNK↓, The increase of JNK and p38 protein phosphorylation was found to be maximal at 12 h
eff↓, N-acetylcysteine (NAC) prevents TQ-induced ROS production

2120- TQ,    Thymoquinone induces apoptosis of human epidermoid carcinoma A431 cells through ROS-mediated suppression of STAT3
- in-vitro, Melanoma, A431
ROS↑, The induction of intracellular reactive oxygen species (ROS) by TQ was evaluated by 2',7'-dichlorofluorescein diacetate staining.
Apoptosis↑, Treatment of A431 cells with TQ-induced apoptosis, which was associated with the induction of p53 and Bax, inhibition of Mdm2, Bcl-2, and Bcl-xl expression, and activation of caspase-9, -7, and -3
P53↑,
BAX↑,
MDM2↓,
Bcl-2↓,
Bcl-xL↓,
Casp9↑,
Casp7↑,
Casp3↑,
STAT3↓, Moreover, the expression of STAT3 target gene products, cyclin D1 and survivin, was attenuated by TQ treatment.
cycD1↓,
survivin↓,
eff↓, The generation of ROS was increased during TQ-induced apoptosis, and the pretreatment of N-acetyl cysteine, a ROS scavenger, reversed the apoptotic effect of TQ

2098- TQ,    Anticancer activity of Nigella sativa (black seed) and its relationship with the thermal processing and quinone composition of the seed
- in-vitro, Colon, MC38 - in-vitro, lymphoma, L428
NF-kB↓, effect of the different methods of thermal processing on the ability of the obtained NS oil to inhibit the nuclear factor kappa B (NF-κB) pathway was then investigated in Hodgkin’s lymphoma (L428) cells.
eff↑, heating the NS seeds to 50°C, 100°C, or 150°C produced oil with a strong ability to inhibit tumor cell growth;
eff↓, no heating or heating to 25°C had a mild antiproliferative effect; and heating to 200°C or 250°C had no effect.

2106- TQ,    Cancer: Thymoquinone antioxidant/pro-oxidant effect as potential anticancer remedy
- Review, Var, NA
Apoptosis↑, The anticancer power of TQ is accomplished by several aspects; including promotion of apoptosis, arrest of cell cycle and ROS generation.
TumCCA↑,
ROS↑,
*Catalase↑, activation of antioxidant cytoprotective enzymes including, CAT, SOD, glutathione reductase (GR) [80], glutathione-S-transferase (GST) [81] and glutathione peroxidase (GPx) - scavenging H2O2 and superoxide radicals and preventing lipid peroxidation
*SOD↑,
*GR↑,
*GSTA1↓,
*GPx↑,
*H2O2↓,
*ROS↓,
*lipid-P↓,
*HO-1↑, application of TQ to HaCaT (normal) cells promoted the expression of HO-1 in a concentration and time-dependent pattern
p‑Akt↓, TQ could induce ROS which provoked phosphorylation and activation of Akt and AMPK-α
AMPKα↑,
NK cell↑, TQ was outlined to enhance natural killer (NK) cells activity
selectivity↑, Many researchers have noticed that the growth inhibitory potential of TQ is particular to cancer cells
Dose↝, Moreover, TQ has a dual effect in which it can acts as both pro-oxidant and antioxidant in a dose-dependent manner; it acts as an antioxidant at low concentration whereas, at higher concentrations it possess pro-oxidant property
eff↑, Pro-oxidant property of TQ occurs in the presence of metal ions including copper and iron which induce conversion of TQ into semiquinone. This leads to generation of reactive oxygen species (ROS) causing DNA damage and induction of cellular apoptosis
GSH↓, TQ for one hour resulted in three-fold increase of ROS while reduced GSH level by 60%
eff↓, pre-treatment of cells with N-acetylcysteine, counteracted TQ-induced ROS production and alleviated growth inhibition
P53↑, TQ provokes apoptosis in MCF-7 cancer cells by up regulating the expression of P53 by time-dependent manner.
p‑STAT3↓, TQ inhibited the phosphorylation of STAT3
PI3K↑, via up regulation of PI3K and MPAK signalling pathway
MAPK↑,
GSK‐3β↑, TQ produced apoptosis in cancer cells and modulated Wnt signaling by activating GSK-3β, translocating β-catenin
ChemoSen↑, Co-administration of TQ and chemotherapeutic agents possess greater cytotoxic influence on cancer cells.
RadioS↑, Treatment of cells with both TQ and IR enhanced the antiproliferative power of TQ as observed by shifting the IC50 values for MCF7 and T47D cells from ∼104 and 37 μM to 72 and 18 μM, respectively.
BioAv↓, TQ cannot be used as the primary therapeutic agent because of its poor bioavailability [177,178] and lower efficacy
NRF2↑, TQ to HaCaT cells promoted the expression of HO-1 in a concentration and time-dependent pattern. This was achieved via increasing stabilization of Nrf2

1929- TQ,    Thymoquinone Suppresses the Proliferation, Migration and Invasiveness through Regulating ROS, Autophagic Flux and miR-877-5p in Human Bladder Carcinoma Cells
- in-vitro, Bladder, 5637 - in-vitro, Bladder, T24
tumCV↓, TQ restrains the viability, proliferation, migration and invasion through activating caspase-dependent apoptosis in bladder carcinoma cells
TumCP↓,
TumCI↓,
Casp↑,
ROS↑, mediated by TQ induced ROS increase in bladder carcinoma cells
PD-L1↓, TQ upregulates hsa-miR-877-5p level to reduce PD-L1 expression in 5637 and T24 BC cells
EMT↓, which suppresses the epithelial mesenchymal transition (EMT)
MMP↓, MMP was markedly lowered by TQ in a dose-dependent way
eff↓, MMP was significantly recovered in the combined treatment of TQ and NAC

4326- VitB5,    Cerebral Vitamin B5 (D-Pantothenic Acid) Deficiency as a Potential Cause of Metabolic Perturbation and Neurodegeneration in Huntington’s Disease
- in-vivo, HD, NA
*Risk↓, We measured metabolic perturbations in HD-human brain in a case-control study, identifying pervasive lowering of vitamin B5
*neuroP↑, Pantothenate deficiency could lead to neurodegeneration/dementia in HD that might be preventable by treatment with vitamin B5.
*other?, Vitamin B5 is an essential trace nutrient that exists in the brain at concentrations of up to 50-fold those in plasma
*Ach↑, vitamin B5 participates via acetyl-CoA in the production of steroid hormones and acetylcholine in the brain
*other↝, resemble dementia or psychiatric disorders. Examples include deficiency of water soluble (B-group) vitamins including: thiamine (vitamin B1) [32]; niacin (vitamin B3) [33]; vitamin B6; folate (vitamin B9); [34] and cyanocobalamin (vitamin B12) [35]
*eff↓, However, treatment of common age-related dementias, such as that caused by AD, with preparations containing B-vitamins (folate and vitamin B12) has proven ineffectual [39].
*other↝, Our results point to a possible defect in the mechanism of cerebral uptake and/or storage of vitamin B5, consistent with its lowered concentrations in affected regions of HD brain.

1818- VitK2,    New insights on vitamin K biology with relevance to cancer
- Review, Var, NA
TumCG↓, A few small randomized trials support the concept that vitamin K supplementation can retard cancer development and/or progression
ChemoSen↑, phase 2 randomized placebo-controlled trial in HCC patients demonstrated that MK4 supplementation (45 mg/day orally) enhanced the efficacy of the multi-kinase inhibitor sorafenib
toxicity∅, long term vitamin K supplementation is safe and may offer survival benefit in HCC patients.
OS↑,
BMD↑, Primary Outcomes: Bone density
eff↑, In studies where both forms of the vitamin have been compared, MKs generally exerted more potent anticancer effects than PK.
MMP↓, direct effects on mitochondrial membrane depolarization and reactive oxygen species (ROS)
ROS↑,
eff↓, ROS neutralization by antioxidants (N-acetyl cysteine (NAC) and alpha-tocopherol) or BAK knockdown prevented MK4 mediated mitochondrial disruption and apoptosis
ERK↑, activates ERK, JNK/p38 MAPK
JNK↑,
p38↑,
Cyt‑c↑, cytochrome c release
Casp↑, caspase activation
ATP↓, reducing ATP production and increasing lactate production
lactateProd↑,
AMPK↑, which activates AMPK
Rho↓, via inhibition of RhoA
TumCG↓, mouse xenograft studies, treatment with MK4 administered in water at a calculated dose of 20 mg/kg/d significantly reduced growth of established HCCs
BioAv↑, Phylloquinone (K1) is the major dietary form, but it is converted into menaquinone (K2) in tissues.
cardioP↑, optimal vitamin K status is common in adults and may contribute to chronic diseases such as osteoporosis, type 2 diabetes and cardiovascular disease.
Risk↓, Observational studies suggest that low vitamin K intake increases cancer risk(more lowers risk)

1214- VitK2,    Vitamin K2 promotes PI3K/AKT/HIF-1α-mediated glycolysis that leads to AMPK-dependent autophagic cell death in bladder cancer cells
- in-vitro, Bladder, T24 - in-vitro, Bladder, J82
Glycolysis↑, Vitamin K2 renders bladder cancer cells more dependence on glycolysis than TCA cycle
GlucoseCon↑, results suggest that Vitamin K2 is able to induce metabolic stress, including glucose starvation and energy shortage, in bladder cancer cells, upon glucose limitation.
lactateProd↑,
TCA↓, Vitamin K2 promotes glycolysis and inhibits TCA cycle in bladder cancer cells
PI3K↑,
Akt↑,
AMPK↑, Vitamin K2 remarkably activated AMPK pathway
mTORC1↓,
TumAuto↑,
GLUT1↑, Vitamin K2 stepwise elevated the expression of some glycolytic proteins or enzymes, such as GLUT-1, Hexokinase II (HK2), PFKFB2, LDHA and PDHK1, in bladder cancer T24
HK2↑,
LDHA↑, Vitamin K2 stepwise elevated the expression of some glycolytic proteins or enzymes, such as GLUT-1, Hexokinase II (HK2), PFKFB2, LDHA and PDHK1, in bladder cancer T24
ACC↓, Vitamin K2 remarkably decreased the amounts of Acetyl coenzyme A (Acetyl-CoA) in T24 cells
PDH↓, suggesting that Vitamin K2 inactivates PDH
eff↓, Intriguingly, glucose supplementation profoundly abrogated AMPK activation and rescued bladder cancer cells from Vitamin K2-triggered autophagic cell death.
cMyc↓, c-MYC protein level was also significantly reduced in T24 cells following treatment with Vitamin K2 for 18 hours
Hif1a↑, Besides, the increased expression of GLUT-1, HIF-1α, p-AKT and p-AMPK were also detected in Vitamin K2-treated tumor group
p‑Akt↑,
eff↓, 2-DG, 3BP and DCA-induced glycolysis attenuation significantly prevented metabolic stress and rescued bladder cancer cells from Vitamin K2-triggered AMPK-dependent autophagic cell death
eff↓, inhibition of PI3K/AKT and HIF-1α notably attenuated Vitamin K2-upregulated glycolysis, indicating that Vitamin K2 promotes glycolysis in bladder cancer cells via PI3K/AKT and HIF-1α signal pathways.
eff↓, (NAC, a ROS scavenger) not only alleviated Vitamin K2-induced AKT activation and glycolysis promotion, but also significantly suppressed the subsequent AMPK-dependent autophagic cell death.
eff↓, glucose supplementation not only restored c-MYC expression, but also rescued bladder cancer cells from Vitamin K2-triggered AMPK-dependent autophagic cell death
ROS↑, under glucose limited condition, the increased glycolysis inevitably resulted in metabolic stress, which augments ROS accumulation due to lack of glucose for sustained glycolysis.

2285- VitK2,    New insights into vitamin K biology with relevance to cancer
- Review, Var, NA
Risk↓, Vitamin K intake has been inversely associated with cancer incidence and mortality in observational studies
AntiCan↑, MK4 supplementation on bone loss in women with viral liver cirrhosis.Over 8 years of follow-up, the risk ratio for the development of HCC in the MK4 group compared with the control group was 0.20
eff↑, phase 2 randomized placebo-controlled trial in HCC patients demonstrated that MK4 supplementation (45 mg/day orally) enhanced the efficacy of the multi-kinase inhibitor sorafenib
MMP↓, MK4 mediated apoptosis may also involve binding of MK4 to pro-apoptotic BAK, direct effects on mitochondrial membrane depolarization and reactive oxygen species (ROS)
ROS↑,
Cyt‑c↑, MK4 covalently bound to BAK induces decrease in MMP and cytochrome c release.
eff↓, ROS production can be blocked by N-acetyl-cysteine (NAC) and alpha-tocopherol which can ultimately block MK4 mediated apoptosis.
SXR↑, Activation of SXR by MK4 (The loss of UBIAD1 in prostate cancer cells reduced MK4 synthesis which in turn decreased SXR transcriptional regulation)

2280- VitK2,    Vitamin K2 induces non-apoptotic cell death along with autophagosome formation in breast cancer cell lines
- in-vitro, BC, MDA-MB-231 - in-vitro, BC, MDA-MB-468 - in-vitro, AML, HL-60
ROS↑, ROS production by VK2 seems to be located up-stream in the molecular machinery for both the types of cell death execution
p62↓, decreased expression of p62, a substrate of autophagy, was observed during the exposure to VK2
eff↓, In the presence of NAC and melatonin, the cytotoxic effect by VK2 was significantly suppressed in both cell lines.

2279- VitK2,    Vitamin K2 Induces Mitochondria-Related Apoptosis in Human Bladder Cancer Cells via ROS and JNK/p38 MAPK Signal Pathways
- in-vitro, Bladder, T24 - in-vitro, Bladder, J82 - in-vitro, Nor, HEK293 - in-vitro, Nor, L02 - in-vivo, NA, NA
MMP↓, Vitamin K2 induced apoptosis in bladder cancer cells through mitochondria pathway including loss of mitochondria membrane potential, cytochrome C release and caspase-3 cascade.
Cyt‑c↑,
Casp3↑,
p‑JNK↑, phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAPK was detected in Vitamin K2-treated cells
p‑p38↑,
ROS↑, generation of reactive oxygen species (ROS) was detected in bladder cancer cells, upon treatment of vitamin K2
eff↓, the anti-oxidant N-acetyl cysteine (NAC) almost blocked the Vitamin K2-triggered apoptosis
tumCV↓, Vitamin K2 significantly decreased the viability of human bladder cancer T24, J82 and EJ cells in a dose- and time-dependent manner
selectivity↑, On the other hand, viability of human normal cells (L02 and HEK293) was minimally affected after exposed to high concentration (100 μM) of Vitamin K2
*toxicity↓,
TumVol↓, in nude mice, vitamin K2 remarkably inhibited the tumor growth and the tumor volume was gradually reduced after the 11th day, compared with the sustained growth of control group.

1839- VitK3,    Vitamin K3 derivative inhibits androgen receptor signaling in targeting aggressive prostate cancer cells
- in-vitro, Pca, NA
TumCP↓, VK3-OCH3 significantly inhibits the proliferation of both RC77-T and MDA-PCa-2b African American PCa cells and promotes apoptosis
Apoptosis↑,
TumCCA↑, blocking the cell cycle at G0
ROS↑, associated with the production of free radicals, such as intracellular and mitochondrial reactive oxygen species (ROS)
eff↓, antioxidants such as N-Acetylcysteine (NAC) and Glutathione (GSH) effectively negated the oxidative stress induced by VK3-OCH3 on PCa cell lines
AR↓, VK3-OCH3 reduces the expression of androgen receptor, TRX2, and anti-apoptotic signaling molecules such as Bcl-2 and TCTP
Trx↓,
Bcl-2↓,

2427- Wog,    Anti-cancer natural products isolated from chinese medicinal herbs
- Review, Var, NA
NO↓, Wogonin has been widely used in the treatment of various inflammatory diseases owing to its inhibition of nitric oxide (NO), prostaglandin E2 and pro-inflammatory cytokines production
PGE2↓,
COX2↓, as well as its reduction of cyclooxygenase-2 (COX-2)
Ca+2↑, Wogonin may also directly activate the mitochondrial Ca2+ channel uniporter and enhance Ca2+ uptake, resulting in Ca2+ overload and mitochondrial damage
mtDam↑,
*toxicity↓, wogonin imposes minor or almost no toxicity on normal peripheral T cells
eff↑, synergistic effect of wogonin on chemotherapy drugs
eff↓, However, other P-gp substrates, such as doxorubicin and vinblastine, do not show any synergistic effect


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 219

Results for Effect on Cancer/Diseased Cells:
12LOX↓,1,   ACC↓,2,   ACC↑,1,   ACLY↓,1,   ADAM17↓,1,   ADP:ATP↑,1,   AIF↑,5,   Akt↓,13,   Akt↑,1,   p‑Akt↓,9,   p‑Akt↑,1,   ALAT∅,1,   ALDH↓,1,   AMPK↑,9,   p‑AMPK↑,3,   AMPKα↑,2,   angioG↓,10,   angioG↑,3,   AntiCan↑,11,   antiOx↓,1,   antiOx↑,4,   AntiTum↑,1,   AP-1↓,1,   Apoptosis↓,3,   Apoptosis↑,74,   mt-Apoptosis↑,2,   AR↓,1,   AST∅,1,   ATF4↑,3,   ATF6↑,1,   ATG5↑,2,   ATG7↑,1,   ATP↓,7,   i-ATP↑,1,   BAD↑,3,   Bak↑,4,   BAX↓,3,   BAX↑,35,   Bax:Bcl2↑,13,   BBB↑,1,   Bcl-2↓,38,   Bcl-2↑,2,   Bcl-2∅,1,   Bcl-xL↓,11,   Beclin-1↑,5,   BID↑,4,   BIM↑,3,   BioAv↓,8,   BioAv↑,5,   BioAv∅,1,   BioEnh↑,1,   BMD↑,1,   BMI1↓,2,   BNIP3?,2,   Ca+2↓,4,   Ca+2↑,13,   Ca+2↝,1,   i-Ca+2?,1,   i-Ca+2↑,1,   CaMKII ↓,1,   cardioP↑,1,   CardioT↓,1,   Casp↑,15,   Casp12?,1,   Casp12↑,1,   Casp2↑,1,   Casp3↓,2,   Casp3↑,49,   cl‑Casp3↑,12,   proCasp3↓,2,   proCasp3↑,1,   Casp7↑,6,   Casp8↑,12,   Casp8∅,2,   cl‑Casp8↑,1,   Casp9↑,33,   cl‑Casp9↑,7,   proCasp9↓,1,   Catalase↓,1,   CD24↓,1,   CD4+↑,2,   CD44↓,4,   CD8+↑,2,   cDC2↓,1,   CDC25↓,5,   Cdc42↑,1,   CDK1↓,1,   p‑CDK1↑,1,   CDK2↓,4,   CDK4↓,5,   CDK4↑,1,   CDK6↓,1,   CDK6↑,1,   CellMemb↓,1,   cFLIP↓,4,   chemoP↑,4,   ChemoSen↓,1,   ChemoSen↑,29,   ChemoSideEff↓,2,   CHK1↓,1,   Chk2↑,1,   Chl∅,1,   CHOP↑,8,   citrate↓,1,   cMET↓,1,   cMYB↓,1,   cMyc↓,4,   COX2↓,4,   COX2↑,1,   CPT1A↓,1,   CSCs↓,4,   Cupro↑,1,   cycA1↓,3,   cycA1↑,2,   CycB↓,5,   CycB↑,3,   cycD1↓,15,   cycD1↑,1,   cycE↓,4,   Cyt‑c↑,33,   DJ-1↓,1,   DNA-PK↑,2,   DNAdam↓,1,   DNAdam↑,17,   DNMT1↑,1,   DNMTs↓,2,   Dose?,2,   Dose↓,2,   Dose↑,5,   Dose↝,9,   Dose∅,9,   DR4↑,2,   DR4∅,1,   DR5↑,9,   E-cadherin↑,4,   E2Fs↓,1,   ECAR↓,3,   eff↓,223,   eff↑,84,   eff↝,6,   EGFR↓,6,   EGR1↑,1,   eIF2α↑,2,   p‑eIF2α↑,5,   EMT↓,4,   Endon↑,1,   EPR↑,1,   ER Stress↓,1,   ER Stress↑,23,   ER Stress↝,1,   ER(estro)↓,1,   ERK↓,5,   ERK↑,5,   p‑ERK↓,1,   p‑ERK↑,3,   e-ERK↑,1,   FADD↑,3,   Fap1↓,1,   Fas↑,1,   FasL↑,5,   FASN↓,1,   FASN↑,1,   Fenton↑,2,   Ferritin↓,1,   Ferroptosis↑,4,   FOSB↑,1,   FOXO3↑,2,   FTH1↓,3,   GCLM↓,1,   GlucoseCon↓,4,   GlucoseCon↑,1,   GlucoseCon∅,1,   GLUT1↓,5,   GLUT1↑,1,   GLUT3↓,1,   Glycolysis↓,11,   Glycolysis↑,1,   GPx↓,2,   GPx4↓,5,   GRP78/BiP↑,8,   GSDMD↑,1,   GSDME↑,1,   GSDME-N↑,1,   GSH↓,20,   GSH∅,1,   GSH/GSSG↓,5,   GSK‐3β↓,1,   GSK‐3β↑,1,   p‑GSK‐3β↓,1,   GSTA1↓,1,   GSTs↓,1,   GSTZ1∅,1,   GutMicro↝,1,   H2O2?,1,   H2O2↑,7,   mt-H2O2↑,1,   H3↓,1,   p‑H3↑,1,   Half-Life↓,3,   Half-Life∅,2,   HDAC↓,7,   HDAC1↓,1,   HDAC10↓,1,   hepatoP↑,1,   HER2/EBBR2↓,1,   Hif1a↓,9,   Hif1a↑,2,   HK2↓,8,   HK2↑,1,   HO-1↓,1,   HO-1↑,2,   HO-2↑,1,   HSF1↓,1,   HSP70/HSPA5↓,1,   HSP70/HSPA5↑,1,   HSPs↑,1,   HSPs∅,1,   hTERT↓,3,   IAP1↓,2,   IAP2↓,1,   ICD↑,1,   IFN-γ↑,1,   IGF-1↓,2,   IGF-1R↓,1,   Igs↑,1,   IKKα↓,2,   IKKα↑,2,   p‑IKKα↓,1,   IL1β↓,3,   IL2↓,1,   IL2↑,1,   IL6↓,4,   IL8↓,1,   Inflam↓,1,   iNOS↓,1,   IRAK4↓,1,   Iron↑,2,   i-Iron↑,1,   JAK1?,1,   p‑JAK1↓,1,   JAK2↓,2,   p‑JAK2↓,2,   JNK↓,2,   JNK↑,11,   p‑JNK↑,4,   Ki-67↓,2,   lactateProd↓,6,   lactateProd↑,3,   lactateProd∅,1,   LAMP1?,1,   LC3‑Ⅱ/LC3‑Ⅰ↑,2,   LC3B↑,2,   LC3B-II↑,5,   LC3II↑,6,   LC3s↑,1,   LDH?,1,   LDH↑,1,   LDHA↓,4,   LDHA↑,1,   LEF1↓,1,   lipid-P↓,1,   lipid-P↑,7,   LOX1↓,1,   pol-M1↑,1,   pol-M2 MC↓,1,   MAPK↑,6,   p‑MAPK↑,2,   Mcl-1↓,4,   MDA↓,1,   MDA↑,4,   MDM2↓,3,   MEK↓,1,   miR-139-5p↑,1,   miR-22↑,1,   miR-30a-5p↑,1,   mitResp↓,3,   mitResp↑,1,   MKP1↓,1,   MKP2↓,1,   MLKL↑,3,   p‑MLKL↓,1,   MMP?,1,   MMP↓,60,   MMP1↓,1,   MMP2↓,8,   proMMP2↓,1,   MMP3↓,1,   MMP7↓,1,   MMP9↓,8,   MMPs↓,3,   MPT↑,2,   mtDam↑,11,   mTOR↓,8,   mTOR↑,1,   p‑mTOR↓,4,   mTORC1↓,2,   mTORC2↑,1,   N-cadherin↓,1,   NAD↓,1,   NADPH↓,1,   NADPH/NADP+↓,1,   NCOA4↑,1,   NDRG1↑,1,   Necroptosis↑,6,   necrosis↑,1,   neuroP↑,3,   NF-kB↓,20,   NF-kB↑,1,   NK cell↑,2,   NKG2D↑,1,   NO↓,1,   NO↑,3,   NOXA↑,1,   NRF2↑,7,   p‑NRF2↑,1,   OCR↓,4,   OCR↑,1,   OS↑,5,   other↓,1,   other↑,3,   other↝,2,   other∅,1,   OXPHOS↓,1,   OXPHOS↑,1,   OXPHOS⇅,1,   P-gp↓,1,   p19↑,1,   P21↓,1,   P21↑,15,   p27↑,4,   p38↑,9,   p‑p38↑,4,   P53↑,15,   P53∅,1,   p‑P53↑,2,   p62↓,4,   p62↑,5,   p65↓,2,   p70S6↓,2,   p85S6K↓,1,   Paraptosis↑,3,   PARK2↑,1,   PARP↓,1,   PARP↑,2,   p‑PARP↑,1,   cl‑PARP↑,33,   proPARP↓,1,   cl‑PARP1↑,1,   PCNA↓,1,   PD-L1↓,2,   PD-L1↑,1,   PDH↓,2,   PDK1↓,1,   PDKs↓,2,   PERK↑,2,   p‑PERK↑,1,   PFK↓,2,   PFK2?,1,   PFKP↓,1,   PGC-1α↑,1,   PGE2↓,1,   PI3K↓,9,   PI3K↑,2,   p‑PI3K↓,1,   PINK1↑,1,   PKCδ↓,1,   PKM2↓,7,   PPP↓,1,   Prx6↑,1,   PTEN↑,3,   Pyro↑,3,   Pyruv↓,1,   RadioS↑,9,   Raf↓,1,   RB1↑,1,   p‑RB1↓,1,   Rho↓,1,   RIP1↓,2,   RIP1↑,1,   RIP3↑,3,   p‑RIP3↑,2,   Risk↓,3,   Risk↑,1,   Risk∅,1,   ROCK1↓,1,   ROS?,3,   ROS↓,3,   ROS↑,154,   ROS⇅,1,   ROS↝,2,   i-ROS↑,3,   mt-ROS↑,6,   RPM↑,1,   SDH↓,3,   selectivity↓,1,   selectivity↑,40,   selectivity∅,1,   SETBP1↓,1,   Shh↓,1,   SIRT1↓,3,   SIRT1↑,2,   SIRT3↑,1,   SLC12A5↓,2,   Slug↓,1,   SMCT1∅,1,   Snail↓,1,   SOD↓,5,   SOD1↑,1,   SOD2↓,1,   SOD2↑,1,   sonoP↑,1,   Sp1/3/4↓,2,   SPARC↑,1,   STAT↓,1,   STAT3↓,7,   p‑STAT3↓,5,   survivin↓,12,   SXR↑,1,   T-Cell↝,1,   TCA?,1,   TCA↓,2,   TCF-4↓,1,   Telomerase↓,2,   TFEB↑,1,   Thiols↓,2,   i-Thiols↓,1,   TIMP2↑,1,   TLR4↓,1,   TNF-α↓,2,   TOP1↑,1,   TOP2↓,1,   TOP2↑,1,   toxicity↓,1,   toxicity↝,2,   toxicity∅,2,   TP53↓,1,   TRAIL↑,2,   TRPV1↑,1,   Trx↓,2,   TrxR↓,5,   TrxR1↓,3,   TrxR2↓,1,   TS↓,1,   TSC2↑,1,   TSP-1↑,1,   TumAuto↓,1,   TumAuto↑,15,   TumCCA?,1,   TumCCA↓,2,   TumCCA↑,47,   TumCD↑,8,   TumCG↓,28,   TumCG↑,3,   TumCI?,1,   TumCI↓,7,   TumCMig↓,9,   TumCP↓,35,   TumCP↑,1,   tumCV?,1,   tumCV↓,27,   tumCV↑,1,   TumMeta↓,6,   TumVol↓,11,   TumW↓,9,   Twist↓,1,   uPA↓,1,   UPR↑,4,   VEGF↓,7,   Vim↓,2,   Weight∅,2,   Wnt↓,2,   XBP-1↑,1,   XIAP↓,4,   β-catenin/ZEB1↓,6,   β-oxidation↓,1,   γH2AX↑,4,   p‑γH2AX↑,3,  
Total Targets: 477

Results for Effect on Normal Cells:
Ach↑,1,   adiP↓,1,   adiP↑,2,   Akt↑,1,   e-Akt↑,1,   ALP↑,1,   AMPK↑,2,   AMPKα↑,1,   angioG↑,1,   antiOx↓,2,   antiOx↑,4,   Apoptosis∅,1,   ARG↑,1,   ATP↓,1,   ATP↑,2,   BAX↓,2,   BAX↑,1,   BBB↑,2,   Bcl-2↓,1,   Bcl-2∅,1,   BioAv?,1,   BioAv↓,2,   BioAv↑,3,   BioAv↝,3,   BMD↑,2,   BOLD↑,1,   Ca+2↓,1,   Ca+2↑,2,   cardioP↑,3,   CardioT↓,1,   Casp12↓,1,   Casp3↑,1,   Casp3∅,1,   cl‑Casp3↓,1,   Catalase↓,1,   Catalase↑,3,   CHOP↓,1,   cognitive↑,3,   COX2↓,1,   CRP↓,1,   Cyt‑c↑,1,   Cyt‑c∅,1,   Dose↝,1,   Dose∅,2,   E2Fs↑,1,   eff↓,23,   eff↑,8,   eff↝,1,   eNOS↑,1,   ER Stress↓,1,   ERK↑,1,   e-ERK↑,1,   FAK↑,1,   glucose↓,1,   glucose↑,1,   GLUT1↑,1,   GLUT4↑,1,   GPx↑,2,   GPx1↑,1,   GPx4↑,1,   GR↑,1,   GRP78/BiP↓,1,   GSH↓,3,   GSH↑,4,   p‑GSK‐3β↑,1,   GSTA1↓,1,   GutMicro↑,1,   H2O2↓,1,   Half-Life↑,1,   Half-Life∅,2,   HDL↑,1,   hepatoP↑,1,   Hif1a↑,1,   HO-1↑,3,   HSPs↑,1,   IGF-1↓,1,   IL10↑,1,   IL1β↓,2,   IL6↓,2,   Inflam↓,7,   iNOS↓,1,   Insulin↓,2,   IronCh↑,1,   LC3II↑,1,   LDH↓,1,   LDL↓,1,   lipid-P↓,1,   MAPK↑,1,   MDA↓,1,   MDA↑,1,   memory↑,1,   mitResp↑,1,   MMP↓,1,   MMP∅,2,   MMP2↑,1,   MMP9↓,1,   MMP9↑,1,   MPT↑,1,   Mst1↓,1,   mTOR↓,1,   neuroP↑,4,   NF-kB↓,3,   NO↓,1,   NO↑,1,   NRF2↑,6,   other?,1,   other↑,2,   other↝,3,   p38↑,1,   p62↑,1,   PGC-1α↑,1,   PI3K↑,1,   PKCδ↑,1,   PTEN↓,1,   RenoP↑,1,   Risk↓,4,   ROS↓,12,   ROS↑,7,   ROS⇅,1,   ROS∅,3,   SCD1↓,1,   selectivity↑,1,   SIRT1↑,1,   SOD↓,1,   SOD↑,4,   SOD1↑,1,   TGF-β↑,1,   TIMP1↑,1,   TNF-α↓,3,   toxicity?,1,   toxicity↓,11,   toxicity↑,2,   toxicity↝,1,   toxicity∅,8,   TumCP↓,1,   tumCV∅,1,   VCAM-1↓,1,   VEGF↑,2,   VGCC↑,1,   VitC↑,1,   Weight↓,1,   Weight∅,1,   Wnt↑,1,   β-catenin/ZEB1↑,1,  
Total Targets: 144

Scientific Paper Hit Count for: eff, efficacy
23 Sulforaphane (mainly Broccoli)
15 Shikonin
14 Magnetic Fields
11 Baicalein
11 Piperlongumine
11 Thymoquinone
10 Ashwagandha
6 Betulinic acid
6 Propolis -bee glue
6 Copper and Cu NanoParticlex
6 Gambogic Acid
5 Berberine
5 Magnetic Field Rotating
5 Parthenolide
5 Silver-NanoParticles
5 Vitamin K2
4 Allicin (mainly Garlic)
4 Apigenin (mainly Parsley)
4 Curcumin
4 EGCG (Epigallocatechin Gallate)
3 Alpha-Lipoic-Acid
3 Citric Acid
3 Fisetin
3 Honokiol
3 Juglone
3 Plumbagin
3 doxorubicin
2 Metformin
2 Artemisinin
2 Vitamin C (Ascorbic Acid)
2 Boron
2 Capsaicin
2 Dichloroacetate
2 diet Methionine-Restricted Diet
2 Folic Acid
2 Luteolin
2 Photodynamic Therapy
2 Hyperthermia
2 Quercetin
2 Phenylbutyrate
2 SonoDynamic Therapy UltraSound
2 Selenium
2 Gold NanoParticles
1 2-DeoxyGlucose
1 Anthocyanins
1 Amodiaquine
1 Andrographis
1 Sorafenib (brand name Nexavar)
1 immunotherapy
1 almonertinib
1 Butyrate
1 5-fluorouracil
1 Caffeic acid
1 Caffeine
1 urea
1 chemodynamic therapy
1 diet FMD Fasting Mimicking Diet
1 diet Short Term Fasting
1 Emodin
1 erastin
1 Exercise
1 Fenbendazole
1 Garcinol
1 Hydrogen Gas
1 HydroxyCitric Acid
1 tamoxifen
1 hydroxychloroquine
1 lambertianic acid
1 Resveratrol
1 Lycopene
1 Methylene blue
1 Matrine
1 Methyl Jasmonate
1 Melatonin
1 Methylsulfonylmethane
1 Myricetin
1 Propyl gallate
1 Rosmarinic acid
1 Scoulerine
1 Auranofin
1 Radiotherapy/Radiation
1 Silymarin (Milk Thistle) silibinin
1 Cisplatin
1 Resiquimod
1 Vitamin B5,Pantothenic Acid
1 VitK3,menadione
1 Wogonin
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:%  Target#:961  State#:%  Dir#:1
  wNotes=on  sortOrder:rid,rpid

 

Home Page