RAS Cancer Research Results

RAS, RAS: Click to Expand ⟱

Source: CGL-CS

Type: oncogene

Family of RAS proteins (KRAS, NRAS, and HRAS) have been well described to cause oncogenic transformation.

- The expression and mutational status of RAS isoforms are critical in several cancers and are generally linked with a poorer prognosis when mutated.

RAS is one of the most frequently activated oncogenic drivers in human cancer. Mutations lock RAS in its GTP-bound active state, making signaling:
-Constitutive
-Growth-factor independent
-Resistant to normal feedback control

Key framing: RAS is a true driver oncogene, not just an amplifier.

Core Oncogenic Pathways Downstream of RAS
RAS sits at the apex of multiple essential signaling cascades:
a. MAPK Pathway (RAF–MEK–ERK)
-Drives proliferation
-Induces cell-cycle genes (Cyclin D, MYC, FOS/AP-1)
-Supports invasion and differentiation blockade

b. PI3K–AKT–mTOR
-Promotes survival and metabolic reprogramming
-Enhances resistance to apoptosis
-Supports protein synthesis and growth

c. RAL-GDS and Others
-Cytoskeletal remodeling
-Vesicle trafficking
-Metastatic behavior

Together, these create a multi-axis growth and survival program.

Scientific Papers found: Click to Expand⟱

5449-

ATV,

Pleiotropic effects of statins: A focus on cancer

NA,

Var,

lipid-P↓, Statins exhibit “pleiotropic” properties that are independent of their lipid-lowering effects.
TumCG↓, preclinical evidence suggests that statins inhibit tumor growth and induce apoptosis in specific cancer cell types.
Apoptosis↑,
ChemoSen↑, statins show chemo-sensitizing effects by impairing Ras family GTPase signaling.
RAS↓,
HMG-CoA↓, Statins are potent, competitive inhibitors of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR).
HMGCR↓,
LDL↓, Statins reduce blood plasma cholesterol levels by decreasing de novo cholesterol biosynthesis and by inducing changes in low density lipoprotein (LDL) receptor expression [2].
toxicity↓, Due to the well-established safety profile of statins, such studies are less expensive than the development of novel drugs.
Risk↓, statin use in cancer patients was associated with reduced cancer-related mortality. The risk of cancer death was significantly lower in postmenopausal women
P21↑, Other proposed mechanisms leading to an increase of p21 levels include the release of promoter-associated histone deacetylase and inhibition of histone deacetylase
HDAC↓,
Bcl-2↓, Statins trigger the intrinsic apoptosis pathway and decrease Bcl-2 protein expression [[154], [155], [156]], increase Bax and BIM protein expression [[156], [157], [158], [159]], and activate several caspases
BAX↑,
BIM↑,
Casp↑,
cl‑PARP↑, thereby increasing cleaved PARP-1 levels.
MMP↓, different tumor cell lines (breast, brain, and lung) showed that simvastatin-induced apoptosis is dependent on decreasing mitochondrial membrane potential and increasing reactive oxygen species (ROS) production
ROS↑,
angioG↓, Statins inhibit angiogenesis and metastasis
TumMeta↓,
PTEN↑, n breast cancer xenografts, simvastatin prevented tumor growth by reducing Akt phosphorylation and BclXL transcription, while simultaneously increasing the transcription of pro-apoptotic/anti-proliferative PTEN
eff↑, In mice, the administration of a combination of celecoxib and atorvastatin was more effective than each individual treatment, and effectively prevented prostate cancer progression from androgen dependent to androgen independent
OS↑, Long-term statin use may improve survival in GBM patients treated with temozolomide chemotherapy
Remission↑, statin use during or after chemotherapy is not associated with improved disease-free-, recurrence-free-, or overall survival in stage II colon cancer patients

2674-

BBR,

Berberine: A novel therapeutic strategy for cancer

Review,

Var,

Review,

IBD,

Inflam↓, anti-inflammatory, antidiabetic, antibacterial, antiparasitic, antidiarrheal, antihypertensive, hypolipidemic, and fungicide.
AntiCan↑, elaborated on the anticancer effects of BBR through the regulation of different molecular pathways such as: inducing apoptosis, autophagy, arresting cell cycle, and inhibiting metastasis and invasion.
Apoptosis↑,
TumAuto↑,
TumCCA↑,
TumMeta↓,
TumCI↓,
eff↑, BBR is shown to have beneficial effects on cancer immunotherapy.
eff↑, BBR inhibited the release of Interleukin 1 beta (IL-1β), Interferon gamma (IFN-γ), Interleukin 6 (IL-6), and Tumor Necrosis Factor-alpha (TNF-α) from LPS stimulated lymphocytes by acting as a dopamine receptor antagonist
CD4+↓, BBR inhibited the proliferation of CD4+ T cells and down-regulated TNF-α and IL-1 and thus, improved autoimmune neuropathy.
TNF-α↓,
IL1↓,
BioAv↓, On the other hand, P-Glycoprotein (P-gp), a secretive pump located in the epithelial cell membrane, restricts the oral bioavailability of a variety of medications, such as BBR. The use of P-gp inhibitors is a common and effective way to prevent this
BioAv↓, Regardless of its low bioavailability, BBR has shown great therapeutic efficacy in the treatment of a number of diseases.
other↓, BBR has been also used as an effective therapeutic agent for Inflammatory Bowel Disease (IBD) for several years
AMPK↑, inhibitory effects on inflammation by regulating different mechanisms such as 5′ Adenosine Monophosphate-Activated Protein Kinase (AMPK. Increase of AMPK
MAPK↓, Mitogen-Activated Protein Kinase (MAPK), and NF-κB signaling pathways
NF-kB↓,
IL6↓, inhibiting the expression of proinflammatory genes such as IL-1, IL-6, Monocyte Chemoattractant Protein 1 (MCP1), TNF-α, Prostaglandin E2 (PGE2), and Cyclooxygenase-2 (COX-2)
MCP1↓,
PGE2↓,
COX2↓,
*ROS↓, BBR protected PC-12 cells (normal) from oxidative damage by suppressing ROS through PI3K/AKT/mTOR signaling pathways
*antiOx↑, BBR therapy improved the antioxidant function of mice intestinal tissue by enhancing the levels of glutathione peroxidase and catalase enzymes.
*GPx↑,
*Catalase↑,
AntiTum↑, Besides, BBR leaves great antitumor effects on multiple types of cancer such as breast cancer,69 bladder cancer,70 hepatocarcinoma,71 and colon cancer.72
TumCP↓, BBR exerts its antitumor activity by inhibiting proliferation, inducing apoptosis and autophagy, and suppressing angiogenesis and metastasis
angioG↓,
Fas↑, by increasing the amounts of Fas receptor (death receptor)/FasL (Fas ligand), ROS, ATM, p53, Retinoblastoma protein (Rb), caspase-9,8,3, TNF-α, Bcl2-associated X protein (Bax), BID
FasL↑,
ROS↑,
ATM↑,
P53↑,
RB1↑,
Casp9↑,
Casp8↑,
Casp3↓,
BAX↑,
Bcl-2↓, and declining Bcl2, Bcl-X, c-IAP1 (inhibitor of apoptosis protein), X-linked inhibitor of apoptosis protein (XIAP), and Survivin levels
Bcl-xL↓,
IAP1↓,
XIAP↓,
survivin↓,
MMP2↓, Furthermore, BBR suppressed Matrix Metalloproteinase-2 (MMP-2), and MMP-9 expression.
MMP9↓,
CycB/CCNB1↓, Inhibition of cyclin B1, cdc2, cdc25c
CDC25↓,
CDC25↓,
Cyt‑c↑, BBR inhibited tumor cell proliferation and migration and induced mitochondria-mediated apoptosis pathway in Triple Negative Breast Cancer (TNBC) by: stimulating cytochrome c release from mitochondria to cytosol
MMP↓, decreased the mitochondrial membrane potential, and enabled cytochrome c release from mitochondria to cytosol
RenoP↑, BBR significantly reduced the destructive effects of cisplatin on the kidney by inhibiting autophagy, and exerted nephroprotective effects.
mTOR↓, U87 cell, Inhibition of m-TOR signaling
MDM2↓, Downregulation of MDM2
LC3II↑, Increase of LC3-II and beclin-1
ERK↓, BBR stimulated AMPK signaling, resulting in reduced extracellular signal–regulated kinase (ERK) activity and COX-2 expression in B16F-10 lung melanoma cells
COX2↓,
MMP3↓, reducing MMP-3 in SGC7901 GC and AGS cells
TGF-β↓, BBR suppressed the invasion and migration of prostate cancer PC-3 cells by inhibiting TGF-β-related signaling molecules which induced Epithelial-Mesenchymal Transition (EMT) such as Bone morphogenetic protein 7 (BMP7),
EMT↑,
ROCK1↓, inhibiting metastasis-associated proteins such as ROCK1, FAK, Ras Homolog Family Member A (RhoA), NF-κB and u-PA, leading to in vitro inhibition of MMP-1 and MMP-13.
FAK↓,
RAS↓,
Rho↓,
NF-kB↓,
uPA↓,
MMP1↓,
MMP13↓,
ChemoSen↑, recent studies have indicated that it can be used in combination with chemotherapy agents

2762-

BetA,

Targeting Effect of Betulinic Acid Liposome Modified by Hyaluronic Acid on Hepatoma Cells In Vitro

in-vitro,

Liver,

HepG2

ROCK1↓, BA, BA-L, and HA-BA-L downregulated the expression of ROCK1, IP3, and RAS in HepG2 cells,
RAS↓,
*BioAv↓, However, its shortcomings, namely poor water solubility and low bioavailability of BA in vivo, limit its clinical application.
BioAv↑, Liposomes can effectively improve the bioavailability of BA. Therefore, the development of liposomal BA delivery can further enhance its efficacy.

5912-

CAR,

Inhibition of TRPM7 by carvacrol suppresses glioblastoma cell proliferation migration and invasion

in-vitro,

GBM,

U87MG

in-vitro,

Nor,

HEK293

TRPM7↓, carvacrol may have therapeutic potential for the treatment of glioblastomas through its inhibition of TRPM7 channels.
tumCV↓, Carvacrol treatment reduced the viability, migration and invasion of U87 cells.
TumCMig↓,
TumCI↓,
MMP2↓, Carvacrol also decreased MMP-2 protein expression and promoted the phosphorylation of cofilin.
p‑Cofilin↑,
RAS↓, carvacrol inhibited the Ras/MEK/MAPK and PI3K/Akt signaling pathways.
MEK↓,
MAPK↓,
PI3K↓,
Akt↓,

424-

CUR,

Curcumin inhibits autocrine growth hormone-mediated invasion and metastasis by targeting NF-κB signaling and polyamine metabolism in breast cancer cells

in-vitro,

BC,

MCF-7

5, 10, 15, 20, 25 and 30 µM, 24, 48 and 72 h

in-vitro,

BC,

MDA-MB-231

Src↓,
p‑STAT1↓, pSTAT-1
p‑Akt↓,
p‑p44↓, p-p44
p‑p42↓, p-p42
RAS↓,
Raf↓, c-RAF
Vim↓,
β-catenin/ZEB1↓,
P53↓,
Bcl-2↓,
Mcl-1↓,
PIAS-3↑,
SOCS-3↑,
SOCS1↑,
ROS↑,
NF-kB↓, NF-kB inactivation, ROS generation and PA depletion in MCF-7, MDA-MB-453 and MDA-MB-231 breast can- cer cells
PAO↑,
SSAT↑,
P21↑,
Bak↑,

1854-

dietFMD,

How Far Are We from Prescribing Fasting as Anticancer Medicine?

Review,

Var,

ChemoSideEff↓, ample nonclinical evidence indicating that fasting can mitigate the toxicity of chemotherapy and/or increase the efficacy of chemotherapy.
ChemoSen↑, Fasting-Induced Increase of the Efficacy of Chemotherapy
IGF-1↓,
IGFBP1↑, biological activity of IGF-1 is further compromised due to increased levels of insulin-like growth factor binding protein 1 (IGFBP1)
adiP↑, increased levels of adiponectin stimulate the fatty acid breakdown.
glyC↓, After depletion of stored glycogen, which occurs usually 24 h after initiation of fasting, the fatty acids serve as the main fuels for most tissues
E-cadherin↑, upregulation of E-cadherin expression via activation of c-Src kinase
MMPs↓, decrease of cytokines, chemokines, metalloproteinases, growth factors
Casp3↑, increase of level of activated caspase-3
ROS↑, it is postulated that the beneficial effects of fasting are ascribed to rapid metabolic and immunological response, triggered by a temporary increase in oxidative free radical production
ATP↓, Glucose deprivation leads to ATP depletion, resulting in ROS accumulation
AMPK↑, Additionally, ROS activate AMPK
mTOR↓, Under conditions of glucose deprivation, AMPK inhibits mTORC1
ROS↑, Beyond glucose deprivation, another mechanism increasing ROS levels is the AA (amino acids) starvation
Glycolysis↓, Indeed, in cancer cells, limited glucose sources impair glycolysis, decrease glycolysis-based NADPH production due to reduced utilization of the pentose phosphate pathway [88,89,90,91],
NADPH↓,
OXPHOS↝, and shift the metabolism from glycolysis to oxidative phosphorylation (OXPHOS) (“anti-Warburg effect”), leading to ROS overload [92,93,94,95].
eff↑, Fasting compared to long-term CR causes a more profound decrease in insulin (90% versus 40%, respectively) and blood glucose (50% versus 25%, respectively).
eff↑, FMD have been demonstrated to result in alterations of the serum levels of IGF-I, IGFBP1, glucose, and ketone bodies reminiscent of those observed in fasting
*RAS↓, A plausible explanation of the differential protective effect of fasting against chemotherapy is the attenuation of the Ras/MAPK and PI3K/Akt pathways downstream of decreased IGF-1 in normal cells
*MAPK↓,
*PI3K↓,
*Akt↓,
eff↑, Starvation combined with cisplatin has been shown in vitro to protect normal cells, promoting complete arrest of cellular proliferation mediated by p53/p21 activation in AMPK-dependent and ATM-independent manner
ROS↑, generation of ROS due to paradoxical activation of the AKT/S6K, partially via the AMPK-mTORC1 energy-sensing pathways malignant cells
Akt↑, cancer cells
Casp3↑, combination of fasting and chemotherapy was in part ascribed to enhanced apoptosis due to activation of caspase 3

5067-

dietFMD,

Fasting-mimicking diet potentiates anti-tumor effects of CDK4/6 inhibitors against breast cancer by suppressing NRAS- and IGF1-mediated mTORC1 signaling

in-vitro,

BC,

mTORC1↓, While fasting-mimicking diet (FMD) enhances the activity of anticancer agents by inhibiting the mTORC1 signaling
IGF-1↓, FMD cooperated with CDK4/6i to suppress the levels of IGF1 and RAS.
RAS↓,

649-

EGCG,

CUR,

PI,

Targeting Cancer Hallmarks with Epigallocatechin Gallate (EGCG): Mechanistic Basis and Therapeutic Targets

Review,

Var,

*BioEnh↑, increase EGCG bioavailability is using other natural products such as curcumin and piperine
EGFR↓,
HER2/EBBR2↓,
IGF-1↓,
MAPK↓,
ERK↓, reduction in ERK1/2 phosphorylation
RAS↓,
Raf↓, Raf-1
NF-kB↓, Numerous investigations have proven that EGCG has an inhibitory effect on NF-κB
p‑pRB↓, EGCG were displayed to reduce the phosphorylation of Rb, and as a result, cells were arrested in G1 phase
TumCCA↑, arrested in G1 phase
Glycolysis↓, EGCG has been found to inhibit key enzymes involved in glycolysis, such as hexokinase and pyruvate kinase, thereby disrupting the Warburg effect and inhibiting tumor cell growth
Warburg↓,
HK2↓,
Pyruv↓,

5055-

Ex,

Why exercise has a crucial role in cancer prevention, risk reduction and improved outcomes

Review,

Var,

OS↑, In 2008, a cohort study of breast cancer survivors identified that patients who consistently exercised for greater than 2.5 hours per week following diagnosis had a greater than 60% reduction in the risk of all deaths compared with patients who were
IGF-1↓, Table 1, IGF1 Decreased levels, IGFBP3 Increased levels
IGFBP3↑,
BRCA1↑, BRCA1 Increased expression
BRCA2↑, BRCA2 Increased expression
RAS↓, RAS family oncogenes Suppressed activity
P53↑, P53 Enhanced activity
HSPs↑, Heat shock proteins Enhanced activity
Leptin↓, Leptin Reduced activity
Irisin↓, Irisin Enhanced activity
Resistin↓, Resistin Reduced activity
NK cell↑, NK cells Enhanced activity
CRP↓, C-reactive protein, interleukin-6, TNFα Reduced activity
IL6↓,
TNF-α↓,
PGE1↓, Prostaglandins Reduced activity
COX2↓, Cox-2 Reduced activity
*GSH↑, Glutathione, Catalase and Superoxide dismutase Increased activity
*Catalase↑,
*SOD↑,
*monoA↑, Monoamines Higher levels
*EndoR↑, Endorphins Increased release
*testos↑, testosterone increases immediately after vigorous exercise in some but not all studies. lasting for 20–60 minutes post-exercise
ROS↑, Physical activity, especially if strenuous, produces reactive oxidative species (ROS)
QoL↑, Adverse cancer-related symptoms, which have been shown to be alleviated by exercise, include fatigue, muscle weakness, thromboembolism, weight gain, loss of bone density, quality of life (QOL), psychological distress, incontinence and sexual dysfunct
BMD↑, the rate of decline in BMD was significantly less in the resistance exercise group, with a greater benefit seen in the aerobic exercise group
BowelM↑, Exercise reduces bowel transit time and ameliorates constipation and its associated abdominal cramps

2827-

FIS,

The Potential Role of Fisetin, a Flavonoid in Cancer Prevention and Treatment

Review,

Var,

*antiOx↑, effective antioxidant, anti-inflammatory
*Inflam↓,
neuroP↑, neuro-protective, anti-diabetic, hepato-protective and reno-protective potential.
hepatoP↑,
RenoP↑,
cycD1/CCND1↓, Figure 3
TumCCA↑,
MMPs↓,
VEGF↓,
MAPK↓,
NF-kB↓,
angioG↓,
Beclin-1↑,
LC3s↑,
ATG5↑,
Bcl-2↓,
BAX↑,
Casp↑,
TNF-α↓,
Half-Life↓, Fisetin was given at an effective dosage of 223 mg/kilogram intraperitoneally in mice. The plasma concentration declined biophysically, with a rapid half-life of 0.09 h and a terminal half-life of 3.1 h,
MMP↓, Fisetin powerfully improved apoptotic cells and caused the depolarization of the mitochondrial membrane.
mt-ROS↑, Fisetin played a role in the induction of apoptosis, independently of p53, and increased mitochondrial ROS generation.
cl‑PARP↑, fisetin-induced sub-G1 population as well as PARP cleavage.
CDK2↓, Moreover, the activities of cyclin-dependent kinases (CDK) 2 as well as CDK4 were decreased by fisetin and also inhibited CDK4 activity in a cell-free system, demonstrating that it might directly inhibit the activity of CDK4
CDK4↓,
Cyt‑c↑, Moreover, release of cytochrome c and Smac/Diablo was induced by fisetin
Diablo↑,
DR5↑, Fisetin caused an increase in the protein levels of cleaved caspase-8, DR5, Fas ligand, and TNF-related apoptosis-inducing ligand
Fas↑,
PCNA↓, Fisetin decreased proliferation-related proteins such as PCNA, Ki67 and phosphorylated histone H3 (p-H3) and decreased the expression of cell growth
Ki-67↓,
p‑H3↓,
chemoP↑, Paclitaxel treatment only showed more toxicity to normal cells than the combination of flavonoids with paclitaxel, suggesting that fisetin might bring some safety against paclitaxel-facilitated cytotoxicity.
Ca+2↑, Fisetin encouraged apoptotic cell death via increased ROS and Ca2+, while it increased caspase-8, -9 and -3 activities and reduced the mitochondrial membrane potential in HSC3 cells.
Dose↝, After fisetin treatment at 40 µM, invasion was reduced by 87.2% and 92.4%, whereas after fisetin treatment at 20 µM, invasion was decreased by 52.4% and 59.4% in SiHa and CaSki cells, respectively
CDC25↓, This study proposes that fisetin caused the arrest of the G2/M cell cycle via deactivating Cdc25c as well Cdc2 via the activation of Chk1, 2 and ATM
CDC2↓,
CHK1↑,
Chk2↑,
ATM↑,
PCK1↓, fisetin decreases the levels of SOS-1, pEGFR, GRB2, PKC, Ras, p-p-38, p-ERK1/2, p-JNK, VEGF, FAK, PI3K, RhoA, p-AKT, uPA, NF-ĸB, MMP-7,-9 and -13, whereas it increases GSK3β as well as E-cadherin in U-2 OS
RAS↓,
p‑p38↓,
Rho↓,
uPA↓,
MMP7↓,
MMP13↓,
GSK‐3β↑,
E-cadherin↑,
survivin↓, whereas those of survivin and BCL-2 were reduced in T98G cells
VEGFR2↓, Fisetin inhibited the VEGFR expression in Y79 cells as well as the angiogenesis of a tumor.
IAP2↓, The downregulation of cIAP-2 by fisetin
STAT3↓, fisetin induced apoptosis in TPC-1 cells via the initiation of oxidative damage and enhanced caspases expression by downregulating STAT3 and JAK 1 signaling
JAK1↓,
mTORC1↓, Fisetin acts as a dual inhibitor of mTORC1/2 signaling,
mTORC2↓,
NRF2↑, Moreover, In JC cells, the Nrf2 expression was gradually increased by fisetin from 8 h to 24 h

2883-

HNK,

Honokiol targets mitochondria to halt cancer progression and metastasis

Review,

Var,

ChemoSen↑, Combination of HNK with many traditional chemotherapeutic drugs as well as radiation sensitizes cancer cells to apoptotic death
BBB↓, HNK is also capable of crossing the BBB
Ca+2↑, HNK promotes human glioblastoma cancer cell apoptosis via regulation of Ca(2+) channels
Cyt‑c↑, release of mitochondrial cytochrome c and activation of caspase-3
Casp3↑,
chemoPv↑, potent chemopreventive agent against lung SCC development in a carcinogen-induced lung SCC murine model
OCR↓, HNK treatment results in a decreased oxygen consumption rate (OCR) in whole intact cells, rapidly, and persistently inhibiting mitochondrial respiration, which leads to the induction of apoptosis
mitResp↓,
Apoptosis↑,
RadioS↑, Honokiol as a chemo- and radiosensitizer
NF-kB↓, HNK as an anticancer drug is its potential to inhibit multiple important survival pathways, such as NF-B and Akt
Akt↓,
TNF-α↓, by inhibiting TNF-induced nerve growth factor IB expression in breast cancer cells
PGE2↓, reduced prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) secretion levels
VEGF↓,
NO↝, HNK inhibits cancer cell migration by targeting nitric oxide and cyclooxygenase-2 or Ras GTPase-activating-like protein (IQGAP1) [
COX2↓,
RAS↓,
EMT↓, HNK can reverse the epithelial-mesenchymal-transition (EMT) process, which is a key step during embryogenesis, cancer invasion, and metastasis,
Snail↓, HNK reduced the expression levels of Snail, N-cadherin and -catenin, which are mesenchymal markers, but increased E-cadherin,
N-cadherin↓,
β-catenin/ZEB1↓,
E-cadherin↑,
ER Stress↑, induction of ER stress
p‑STAT3↓, HNK inhibited STAT3 phosphorylation
EGFR↓, inhibiting EGFR phosphorylation and its downstream signaling pathways such as the mTOR signaling pathway
mTOR↓,
mt-ROS↑, We demonstrated that HNK treatment suppresses mitochondrial respiration and increases generation of ROS in the mitochondria, leading to the induction of apoptosis in lung cancer cells
PI3K↓, inhibition of PI3K/Akt/ mTOR, EMT, and Wnt signaling pathways.
Wnt↓,

2885-

HNK,

Honokiol: a novel natural agent for cancer prevention and therapy

NF-kB↓, Honokiol targets multiple signaling pathways including nuclear factor kappa B (NF-κB), signal transducers and activator of transcription 3 (STAT3), epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (m-TOR)
STAT3↓,
EGFR↓,
mTOR↓,
BioAv↝, honokiol has revealed a desirable spectrum of bioavailability after intravenous administration in animal models, thus making it a suitable agent for clinical trials
Inflam↓, inflammation, proliferation, angiogenesis, invasion and metastasis.
TumCP↓,
angioG↓,
TumCI↓,
TumMeta↓,
cSrc↓, STAT3 inhibition by honokiol has also been correlated with the repression of upstream protein tyrosine kinases c-Src, JAK1 and JAK2
JAK1↓,
JAK2↓,
ERK↓, by inhibiting ERK and Akt pathways (31) or by upregulation of PTEN
Akt↓,
PTEN↑,
ChemoSen↑, Chemopreventive/ chemotherapeutic effects of honokiol in various malignancies: preclinical studies
chemoP↑,
COX2↓, honokiol was found to inhibit UVB-induced expression of cyclooxygenase-2, prostaglandin E2, proliferating cell nuclear antigen and pro-inflammatory cytokines, such as TNF-α, interleukin (IL)-1β and IL-6 in the skin
PGE2↓,
TNF-α↓,
IL1β↓,
IL6↓,
Casp3↑, release of caspases-3, -8 and -9as well as poly (ADP-ribose) polymerase (PARP) cleavage and p53 activation upon honokiol treatment that led to DNA fragmentation
Casp8↑,
Casp9↑,
cl‑PARP↑,
DNAdam↑,
Cyt‑c↑, translocation of cytochrome c to cytosol in human melanoma cell lines
RadioS↑, liposomal honokiol for 24 h showed a higher radiation enhancement ratio (~ two-fold) as compared to the radiation alone,
RAS↓, Honokiol also caused suppression of Ras activation
BBB↑, honokiol could effectively cross BBB and BCSFB and inhibit brain tumor growth
BioAv↓, Due to the concerns about poor aqueous solubility, liposomal formulations of honokiol have been developed and tested for their pharmacokinetics
Half-Life↝, In another comparative study, plasma honokiol concentrations was maintained above 30 and 10 μg/mL for 24 and 48 hours, respectively, in liposomal honokiol-treated mice, whereas it fell quickly (less than 5 μg/mL) by 12 hours in free honokiol-treated
Half-Life↝, free honokiol has poor GIT absorption, bio-transformed in liver to mono-glucuronide honokiol and sulphated mono-hydroxyhonokiol, ~ 50% is secreted in bile, ~ 60-65% plasma protein bound with elimination half life of (t1/2) of 49.05 – 56.24 minutes.
toxicity↓, These studies suggest that honokiol either alone or as a part of magnolia bark extract does not induce toxicity in animal models and thus could be clinically safe

2894-

HNK,

Pharmacological features, health benefits and clinical implications of honokiol

Review,

Var,

Review,

AD,

*BioAv↓, HNK showed poor aqueous solubility due to phenolic hydroxyl groups forming intramolecular hydrogen bonds and poor solubility in water (
*neuroP↑, HNK has the accessibility to reach the neuronal tissue by crossing the BBB and showing neuroprotective effects
*BBB↑,
*ROS↓, fig 2
*Keap1↑,
*NRF2↑,
*Casp3↓,
*SIRT3↑,
*Rho↓,
*ERK↓,
*NF-kB↓,
angioG↓,
RAS↓,
PI3K↓,
Akt↓,
mTOR↓,
*memory↑, oral administration of HNK (1 mg/kg) in senescence-accelerated mice prevents age-related memory and learning deficits
*Aβ↓, in Alzheimer’s disease, HNK significantly reduces neurotoxicity of aggregated Ab
*PPARγ↑, Furthermore, the expression of PPARc and PGC1a was increased by HNK, suggesting its beneficial impact on energy metabolism
*PGC-1α↑,
NF-kB↓, activation of NFjB was suppressed by HNK via suppression of nuclear translocation and phosphorylation of the p65 subunit and further instigated apoptosis by enhancing TNF-a
Hif1a↓, HNK has anti-oxidative properties and can downregulate the HIF-1a protein, inhibiting hypoxia- related signaling pathways
VEGF↓, renal cancer, via decreasing the vascular endothelial growth factor (VEGF) and heme-oxygenase-1 (HO-1)
HO-1↓,
FOXM1↓, HNK interaction with the FOXM1 oncogenic transcription factor inhibits cancer cells
p27↑, HNK treatment upregulates the expression of CDK inhibitor p27 and p21, whereas it downregulates the expression of CDK2/4/6 and cyclin D1/2
P21↑,
CDK2↓,
CDK4↓,
CDK6↓,
cycD1/CCND1↓,
Twist↓, HNK averted the invasion of urinary bladder cancer cells by downregulating the steroid receptor coactivator, Twist1 and Matrix metalloproteinase-2
MMP2↓,
Rho↑, By activating the RhoA, ROCK and MLC signaling, HNK inhibits the migration of highly metastatic renal cell carcinoma
ROCK1↑,
TumCMig↓,
cFLIP↓, HNK can be used to suppress c-FLIP, the apoptosis inhibitor.
BMPs↑, HNK treatment increases the expression of BMP7 protein
OCR↑, HNK might increase the oxygen consumption rate while decreasing the extracellular acidification rate in breast cancer cells.
ECAR↓,
*AntiAg↑, It also suppresses the platelet aggregation
*cardioP↑, HNK is an attractive cardioprotective agent because of its strong antioxidative properties
*antiOx↑,
*ROS↓, HNK treatment reduced cellular ROS production and decreased mitochondrial damage in neonatal rat cardiomyocytes exposed to hypoxia/reoxygenation
P-gp↓, The expres- sion of P-gp at mRNA and protein levels is reduced in HNK treatment on human MDR and MCF-7/ADR breast cancer cell lines

2914-

LT,

Therapeutic Potential of Luteolin on Cancer

Review,

Var,

3–50 µM in vitro

*antiOx↑, As an antioxidant, Luteolin and its glycosides can scavenge free radicals caused by oxidative damage and chelate metal ions
*IronCh↑,
*toxicity↓, The safety profile of Luteolin has been proven by its non-toxic side effects, as the oral median lethal dose (LD50) was found to be higher than 2500 and 5000 mg/kg in mice and rats, respectively, equal to approximately 219.8−793.7 mg/kg in humans
*BioAv↓, One major problem related to the use of flavonoids for therapeutic purposes is their low bioavailability.
*BioAv↑, Resveratrol, which functions as the inhibitor of UGT1A1 and UGT1A9, significantly improved the bioavailability of Luteolin by decreasing the major glucuronidation metabolite in rats
DNAdam↑, Luteolin’s anticancer properties, which involve DNA damage, regulation of redox, and protein kinases in inhibiting cancer cell proliferation
TumCP↓,
DR5↑, Luteolin was discovered to promote apoptosis of different cancer cells by increasing Death receptors, p53, JNK, Bax, Cleaved Caspase-3/-8-/-9, and PARP expressions
P53↑,
JNK↑,
BAX↑,
cl‑Casp3↑,
cl‑Casp8↑,
cl‑Casp9↑,
cl‑PARP↑,
survivin↓, downregulating proteins involved in cell cycle progression, including Survivin, Cyclin D1, Cyclin B, and CDC2, and upregulating p21
cycD1/CCND1↓,
CycB/CCNB1↓,
CDC2↓,
P21↑,
angioG↓, suppress angiogenesis in cancer cells by inhibiting the expression of some angiogenic factors, such as MMP-2, AEG-1, VEGF, and VEGFR2
MMP2↓,
AEG1↓,
VEGF↓,
VEGFR2↓,
MMP9↓, inhibit metastasis by inhibiting several proteins that function in metastasis, such as MMP-2/-9, CXCR4, PI3K/Akt, ERK1/2
CXCR4↓,
PI3K↓,
Akt↓,
ERK↓,
TumAuto↑, can promote the conversion of LC3B I to LC3B II and upregulate Beclin1 expression, thereby causing autophagy
LC3B-II↑,
EMT↓, Luteolin was identified to suppress the epithelial to mesenchymal transition by upregulating E-cadherin and downregulating N-cadherin and Wnt3 expressions.
E-cadherin↑,
N-cadherin↓,
Wnt↓,
ROS↑, DNA damage that is induced by reactive oxygen species (ROS),
NICD↓, Luteolin can block the Notch intracellular domain (NICD) that is created by the activation of the Not
p‑GSK‐3β↓, Luteolin can inhibit the phosphorylation of the GSK3β induced by Wnt, resulting in the prevention of GSK3β inhibition
iNOS↓, Luteolin in colon cancer and the complications associated with it, particularly the decreasing effect on the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2)
COX2↓,
NRF2↑, Luteolin has been identified to increase the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), which is a crucial transcription factor with anticarcinogenic properties related
Ca+2↑, caused loss of the mitochondrial membrane action potential, enhanced levels of mitochondrial calcium (Ca2+),
ChemoSen↑, Luteolin enhanced the effect of one of the most effective chemotherapy drugs, cisplatin, on CRC cells
ChemoSen↓, high dose of Luteolin application negatively affected the oxaliplatin-based chemotherapy in a p53-dependent manner [52]. They suggested that the flavonoids with Nrf2-activating ability might interfere with the chemotherapeutic efficacy of anticancer
IFN-γ↓, decreased the expression of interferon-gamma-(IFN-γ)
RadioS↑, suggested that Luteolin can act as a radiosensitizer, promoting apoptosis by inducing p38/ROS/caspase cascade
MDM2↓, Luteolin treatment was associated with increased p53 and p21 and decreased MDM4 expressions both in vitro and in vivo.
NOTCH1↓, Luteolin suppressed the growth of lung cancer cells, metastasis, and Notch-1 signaling pathway
AR↓, downregulating the androgen receptor (AR) expression
TIMP1↑, Luteolin inhibits the migration of U251MG and U87MG human glioblastoma cell lines by downregulating MMP-2 and MMP-9 and upregulating the tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2.
TIMP2↑,
ER Stress↑, Luteolin caused oxidative stress and ER stress in the Hep3B cells,
CDK2↓, Luteolin’s ability to decrease Akt, polo-like kinase 1 (PLK1), cyclin B1, cyclin A, CDC2, cyclin-dependent kinase 2 (CDK2) and Bcl-xL
Telomerase↓, Luteolin dose-dependently inhibited the telomerase levels and caused the phosphorylation of NF-κB and the target gene of NF-κB, c-Myc to suppress the human telomerase reverse transcriptase (hTERT)
p‑NF-kB↑,
p‑cMyc↑,
hTERT/TERT↓,
RAS↓, Luteolin was found to suppress the expressions of K-Ras, H-Ras, and N-Ras, which are the activators of PI3K
YAP/TEAD↓, Luteolin caused significant inhibition of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ)
TAZ↓,
NF-kB↓, Luteolin was found to have a strong inhibitory effect on the NF-κB
NRF2↓, Luteolin-loaded nanoparticles resulted in a significant reduction in the Nrf2 levels compared to Luteolin alone.
HO-1↓, The expressions of the downstream genes of Nrf2, Ho1, and MDR1 were also reduced, where inhibition of Nrf2 expression significantly increased the cell death of breast cancer cells
MDR1↓,

1807-

NarG,

A Systematic Review of the Preventive and Therapeutic Effects of Naringin Against Human Malignancies

Review,

NA,

AntiTum↑, antitumor ability of naringin
TumCP↓,
tumCV↓,
TumCCA↑,
Mcl-1↓,
RAS↓,
e-Raf↓, suppressing the Ras/Raf/extracellular
VEGF↓,
AntiAg↑,
MMP2↓,
MMP9↓,
TIMP2↑,
TIMP1↑,
p38↓,
Wnt↓,
β-catenin/ZEB1↑,
Casp↑,
P53↑,
BAX↑,
COX2↓,
GLO-I↓,
CYP1A1↑,
lipid-P↓,
p‑Akt↓,
p‑mTOR↓,
VCAM-1↓,
P-gp↓,
survivin↓,
Bcl-2↓,
ROS↑, ↑oxidative stress, Prostate DU145 cell line 50–250 μM
ROS↑, ↑ROS, Stomach (Gastric) AGS cell line, 1–3 mM
MAPK↑,
STAT3↓,
chemoP↑, flavonoids have excellent radical scavenging and iron-chelating properties (Kaiserová et al., 2007), and they can act as an effective modulator for DOX-induced toxicity

5254-

NCL,

The magic bullet: Niclosamide

Review,

Var,

Wnt↓, In particular, niclosamide inhibits multiple oncogenic pathways such as Wnt/β-catenin, Ras, Stat3, Notch, E2F-Myc, NF-κB, and mTOR and activates tumor suppressor signaling pathways such as p53, PP2A, and AMPK.
β-catenin/ZEB1↓,
RAS↓,
STAT3↓,
NOTCH↓,
E2Fs↓,
mTOR↓,
eff↑, Moreover, niclosamide potentially improves immunotherapy by modulating pathways such as PD-1/PDL-1.
PD-1↓,
PD-L1↓, primarily through PD-L1 ligand downregulation in cancer cells.
BioAv↝, The original pharmacokinetics study showed that the maximal serum concentration can reach 0.25-6.0ug/ml (0.76-18.34 µM) following administration of a single 2g dose (11).
toxicity↓, a strong safety profile and tolerability in humans.
BioAv↑, A potential solution to the aforementioned challenge is niclosamide ethanolamine (NEN), a salt form of niclosamide that also functions as a mitochondrial uncoupler with a superior safety profile and enhanced bioavailability
ETC↑, NEN activates the ETC to boost NADH oxidation, thereby leading to an increased intracellular NAD+/NADH ratio and driving the TCA cycle forward.
NADH:NAD↓,
TCA↑,
Warburg↓, leading to a reversal of the Warburg effect and the induction of cellular differentiation
Diff↑,
AMPK↑, figure 3
P53↑,
PP2A↑,
HIF-1↓,
KRAS↓,
Myc↓,
RadioS↑, leading to a reversal of the Warburg effect and the induction of cellular differentiation
ChemoSen↑, Niclosamide has shown synergistic anti-tumor effects with a broad spectrum of chemotherapy drugs.
Dose↝, In this trial, either 500mg or 1000mg niclosamide was given three times daily to patients. However, the maximal plasma concentration ranged from 35.7–82 ng/mL (0.1µM-0.25 µM), a range that failed to be consistently above the minimum effective concent
Dose↑, In contrast, the ongoing clinical trial NCT02807805 is administering 1200 mg of reformulated orally bioavailable niclosamide orally (PO) three times daily to patients, resulting in 0.21µM-0.723 plasma niclosamide concentrations exceeding the therape

5187-

PEITC,

Phenethyl Isothiocyanate Inhibits Migration and Invasion of Human Gastric Cancer AGS Cells through Suppressing MAPK and NF-κB Signal Pathways

in-vitro,

GC,

AGS

TumMeta↓, PEITC can inhibit migration and invasion through the extracellular signal-regulated kinases 1/2 (ERK1/2), protein kinase C (PKC) and nuclear factor-kappaB (NF-κB) signaling pathways in human gastric cells.
ERK↓, PEITC exerted an inhibitory effect on the ERK1/2, mitogen-activated protein kinase kinase 7 (MKK7)
MKK7↓,
PKCδ↓, PKC, Ras homolog gene family, member A (Rho A) and urokinase-type plasminogen activator (uPA), causing the inhibition of matrix metallopeptidase-2 (MMP-2) and -9
Rho↓,
uPA↓,
MMP2↓,
MMP9↓,
RAS↓, PEITC also inhibited Ras, growth factor receptor-bound protein 2 (GRB2), vascular endothelial growth factor (VEGF), focal adhesion kinase (FAK), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), causing inhibition of cell prolifera
VEGF↓,
FAK↓,
iNOS↓,
COX2↓,
TumCP↓,

2946-

PL,

Piperlongumine, a potent anticancer phytotherapeutic: Perspectives on contemporary status and future possibilities as an anticancer agent

Review,

Var,

ROS↑, piperlongumine inhibits cancer growth by resulting in the accumulation of intracellular reactive oxygen species, decreasing glutathione and chromosomal damage, or modulating key regulatory proteins, including PI3K, AKT, mTOR, NF-kβ, STATs, and cycD
GSH↓, reduced glutathione (GSH) levels in mouse colon cancer cells
DNAdam↑,
ChemoSen↑, combined treatment with piperlongumine potentiates the anticancer activity of conventional chemotherapeutics and overcomes resistance to chemo- and radio- therapy
RadioS↑, piperlongumine treatment enhances ROS production via decreasing GSH levels and causing thioredoxin reductase inhibition
BioEnh↑, Moreover, the bioavailability is significantly improved after oral administration of piperlongumine
selectivity↑, It shows selectivity toward human cancer cells over normal cells and has minimal side effects
BioAv↓, ts low aqueous solubility affects its anti-cancer activity by limiting its bioavailability during oral administration
eff↑, encapsulation of piperlongumine in another biocompatible natural polymer, chitosan, has been found to result in pH-dependent piperlongumine release and to enhance cytotoxicity via efficient intracellular ROS accumulation against human gastric carcin
p‑Akt↓, Fig 2
mTOR↓,
GSK‐3β↓,
β-catenin/ZEB1↓,
HK2↓, iperlongumine treatment decreases cell proliferation, single-cell colony-formation ability, and HK2-mediated glycolysis in NSCLC cells via inhibiting the interaction between HK2 and voltage-dependent anion channel 1 (VDAC1)
Glycolysis↓,
Cyt‑c↑,
Casp9↑,
Casp3↑,
Casp7↑,
cl‑PARP↑,
TrxR↓, piperlongumine (4 or 12 mg/kg/day for 15 days) administration significantly inhibits increase in tumor weight and volume with less TrxR1 activity in SGC-7901 cell
ER Stress↑,
ATF4↝,
CHOP↑, activating the downstream ER-MAPK-C/EBP homologous protein (CHOP) signaling pathway
Prx4↑, piperlongumine kills high-grade glioma cells via oxidative inactivation of PRDX4 mediated ROS induction, thereby inducing intracellular ER stress
NF-kB↓, piperlongumine treatment (2.5â5 mg/ kg body weight) decreases the growth of lung tumors via inhibition of NF-ÎºB
cycD1/CCND1↓, decreases expression of cyclin D1, cyclin- dependent kinase (CDK)-4, CDK-6, p- retinoblastoma (p-Rb)
CDK4↓,
CDK6↓,
p‑RB1↓,
RAS↓, piperlongumine downregulates the expression of Ras protein
cMyc↓, inhibiting the activity of other related proteins, such as Akt/NF-ÎºB, c-Myc, and cyclin D1 in DMH + DSS induced colon tumor cells
TumCCA↑, by arresting colon tumor cells in the G2/M phase of the cell cycle
selectivity↑, hows more selective cytotoxicity against human breast cancer MCF-7 cells than human breast epithelial MCF-10A cells
STAT3↓, thus inducing inhibition of the STAT3 signaling pathway in multiple myeloma cells
NRF2↑, Nrf2) activation has been found to mediate the upregulation of heme oxygenase-1 (HO-1) in piperlongumine treated MCF-7 and MCF-10A cells
HO-1↑,
PTEN↑, stimulates ROS accumulation; p53, p27, and PTEN overexpression
P-gp↓, P-gp, MDR1, MRP1, survivin, p-Akt, NF-ÎºB, and Twist downregulation;
MDR1↓,
MRP1↓,
survivin↓,
Twist↓,
AP-1↓, iperlongumine significantly suppresses the expression of transcription factors, such as AP-1, MYC, NF-ÎºB, SP1, STAT1, STAT3, STAT6, and YY1.
Sp1/3/4↓,
STAT1↓,
STAT6↓,
SOX4↑, increased expression of p21, SOX4, and XBP in B-ALL cells
XBP-1↑,
P21↑,
eff↑, combined use of piperlongumine with cisplatin enhances the sensitivity toward cisplatin by inhibiting Akt phosphorylation
Inflam↓, inflammation (COX-2, IL6); invasion and metastasis, such as ICAM-1, MMP-9, CXCR-4, VEGF;
COX2↓,
IL6↓,
MMP9↓,
TumMeta↓,
TumCI↓,
ICAM-1↓,
CXCR4↓,
VEGF↓,
angioG↓,
Half-Life↝, The analysis of the plasma of piperlongumine treated mice (50 mg/kg) after intraperitoneal administration, 1511.9 ng/ml, 418.2 ng/ml, and 41.9 ng/ml concentrations ofplasma piperlongumine were found at 30 minutes, 3 hours, and 24 hours, respecti
BioAv↑, Moreover, the bioavailability is significantly improved after oral administration of piperlongumine

3352-

QC,

A review of quercetin: Antioxidant and anticancer properties

Review,

Var,

*antiOx↑, Quercetin is considered to be a strong antioxidant due to its ability to scavenge free radicals and bind transition metal ions. T
*lipid-P↓, properties of quercetin allow it to inhibit lipid peroxidation
*TNF-α↓, Quercetin significantly inhibited TNF-α production and gene expression in a dose-dependent manner
*NF-kB↓, inhibiting the activation of NF-κβ,
*COX2↓, Quercetin also inhibits the enzymes cyclooxygenase
*IronCh↑, Quercetin also chelates ions of transition metals such as iron which can initiate the formation of oxygen free radicals
P53↓, Quercetin (248 microM) was found to down regulate expression of mutant p53 protein to nearly undetectable levels in human breast cancer cell lines.
TumCCA↑, Quercetin has been found to arrest human leukemic T-cells in the late G1 phase of the cell cycle.
HSPs↓, Quercetin has been found to inhibit production of heat shock proteins in several malignant cell lines, including breast cancer,[52] leukemia,[53] and colon cancer.[
P21↓, Quercetin (10 microM) has been found to inhibit the expression of the p21-ras oncogene in cultured colon cancer cell lines
RAS↓,
ER(estro)↑, Quercetin has been shown to induce ER II expression in both type I estrogen receptor positive (ER+) and type I estrogen receptor negative (ER-) human breast cancer cells
OS?, Animals treated daily with 40 mg/kg quercetin had a 20-percent increase in life span, while those treated with 160 mg/kg rutin had a 50% increase in life span.

3350-

QC,

Quercetin and the mitochondria: A mechanistic view

Review,

NA,

*antiOx↑, antioxidant and anti-inflammatory properties
*Inflam↓,
*NRF2↑, Quercetin is able to activate the master regulator nuclear factor erythroid 2-related factor 2 (Nrf2)
ROS⇅, That is, as a free radical-scavenging antioxidant, quercetin protects cells against DNA damage induced by reactiveoxygen species (ROS), but the oxidized quercetin intermediates (see above) can then react with glutathione (GSH) thereby lowering GSH
*NRF2↑, 10uM (24 h) Mouse primary hepatocytes Activation of Nrf2; ↑HO-1 levels; ↑expression of PPARÎ± and PGC-1Î±
*HO-1↑,
*PPARα↑,
*PGC-1α↑,
*SIRT1↑, Rat hippocampus ↑ SIRT1, PGC-1Î±, NRF-1, and TFAM levels; ATP levels;
*ATP↑,
ATP↓, L1210 and P388 leukemia cells (Suolinna et al., 1975). At least in part, the authors attributed the pro-apoptotic effect of quercetin in these cell lines to its capacity to inhibit ATP synthase, causing a decrease in ATP content.
ERK↓, downregulation of ERK1/2 by quercetin (50-100 uM for 24 or 48 h, combined or not with resveratrol
cl‑PARP↑, NCaP cells ↑PARP cleavage ↑ Caspase-9, caspase-8, and caspase-3 activities
Casp9↑,
Casp8↑,
BAX↑, MDA-MB-231 cells ↑Bax levels, ↓MMP, ↑cytochrome c release, ↑caspase-9 and caspase-3 activities
MMP↓,
Cyt‑c↑,
Casp3↑,
HSP27↓, T98G cells: ↓Hsp27 and Hsp72 contents, ↓Ras and Raf level
HSP72↓,
RAS↓,
Raf↓,

3343-

QC,

Quercetin, a Flavonoid with Great Pharmacological Capacity

Review,

Var,

Review,

AD,

Review,

Arthritis,

*antiOx↑, Quercetin has a potent antioxidant capacity, being able to capture reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive chlorine species (ROC),which act as reducing agents by chelating transition-metal ions.
*ROS↓, Quercetin is a potent scavenger of reactive oxygen species (ROS), protecting the organism against oxidative stress
*angioG↓,
*Inflam↓, anti-inflammatory properties; the ability to protect low-density lipoprotein (LDL) oxidation, and the ability to inhibit angiogenesis;
*BioAv↓, It is known that the bioavailability of quercetin is usually relatively low (0.17–7 μg/mL), less than 10% of what is consumed, due to its poor water solubility (hydrophobicity), chemical stability, and absorption profile.
*Half-Life↑, their slow elimination since their half-life ranges from 11 to 48 h, which could favor their accumulation in plasma after repeated intakes
*GSH↑, Animal and cell studies have demonstrated that quercetin induces the synthesis of GSH
*SOD↑, increase in the expression of superoxide dismutase (SOD), catalase (CAT), and GSH with quercetin pretreatment
*Catalase↑,
*Nrf1↑, quercetin accomplishes this process involves increasing the activity of the nuclear factor erythroid 2-related factor 2 (NRF2), enhancing its binding to the ARE, reducing its degradation
*BP↓, quercetin has been shown to inhibit ACE activity, reducing blood pressure
*cardioP↑, quercetin has positive effects on cardiovascular diseases
*IL10↓, Under the influence of quercetin, the levels of interleukin 10 (IL-10), IL-1β, and TNF-α were reduced.
*TNF-α↓,
*Aβ↓, quercetin’s ability to modulate the enzyme activity in clearing amyloid-beta (Aβ) plaques, a hallmark of AD pathology.
*GSK‐3β↓, quercetin can inhibit the activity of glycogen synthase kinase 3β,
*tau↓, thus reducing tau aggregation and neurofibrillary tangles in the brain
*neuroP↑,
*Pain↓, quercetin reduces pain and inflammation associated with arthritis
*COX2↓, quercetin included the inhibition of oxidative stress, production of cytokines such as cyclooxygenase-2 (COX-2) and proteoglycan degradation, and activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) (Nrf2/HO-1)
*NRF2↑,
*HO-1↑,
*IL1β↓, Mechanisms included decreased levels of TNF-α, IL-1β, IL-17, and monocyte chemoattractant protein-1 (MCP-1)
*IL17↓,
*MCP1↓,
PKCδ↓, studies with human leukemia 60 (HL-60) cells report that concentrations between 20 and 30 µM are sufficient to exert an inhibitory effect on cytosolic PKC activity and membrane tyrosine protein kinase (TPK) activity.
ERK↓, 50 µM resulted in the blockade of the extracellular signal-regulated kinases (ERK1/2) pathway
BAX↓, higher doses (75–100 µM) were used, as these doses reduced the expression of proapoptotic factors such as Bcl-2-associated X protein (Bax) and caspases 3 and 9
cMyc↓, induce apoptosis at concentrations of 80 µM and also causes a downregulation of cellular myelocytomatosis (c-myc) and Kirsten RAt sarcoma (K-ras) oncogenes
KRAS↓,
ROS↓, compound’s antioxidative effect changes entirely to a prooxidant effect at high concentrations, which induces selective cytotoxicity
selectivity↑, On the other hand, when noncancerous cells are exposed to quercetin, it exerts cytoprotective effects;
tumCV↓, decrease cell viability in human glioma cultures of the U-118 MG cell line as well as an increase in death by apoptosis and cell arrest at the G2 checkpoint of the cell cycle.
Apoptosis↑,
TumCCA↑,
eff↑, quercetin combined with doxorubicin can induce multinucleation of invasive tumor cells, downregulate P-glycoprotein (P-gp) expression, increase cell sensitivity to doxorubicin,
P-gp↓,
eff↑, resveratrol, quercetin, and catechin can effectively block the cell cycle and reduce cell proliferation in vivo
eff↑, cotreatment with epigallocatechin gallate (EGCG) inhibited catechol-O-methyltransferase (COMT) activity, decreasing COMT protein content and thereby arresting the cell cycle of PC-3 human prostate cancer cells
eff↑, synergistic treatment of tamoxifen and quercetin was also able to inhibit prostate tumor formation by regulating angiogenesis
eff↑, coadministration of 2.5 μM of EGCG, genistein, and quercetin suppressed the cell proliferation of a prostate cancer cell line (CWR22Rv1) by controlling androgen receptor and NAD (P)H: quinone oxidoreductase 1 (NQO1) expression
CycB/CCNB1↓, It can also downregulate cyclin B1 and cyclin-dependent kinase-1 (CDK-1),
CDK1↓,
CDK4↓, quercetin causes a decrease in cyclins D1/Cdk4 and E/Cdk2 and an increase in p21 in vascular smooth muscle cells
CDK2↓,
TOP2↓, quercetin is known to be a potent inhibitor of topoisomerase II (TopoII), a cell cycle-associated enzyme necessary for DNA replication
Cyt‑c↑, quercetin can induce apoptosis (cell death) through caspase-3 and caspase-9 activation, cytochrome c release, and poly ADP ribose polymerase (PARP) cleavage
cl‑PARP↑,
MMP↓, quercetin induces the loss of mitochondrial membrane potential, leading to the activation of the caspase cascade and cleavage of PARP.
HSP70/HSPA5↓, apoptotic effects of quercetin may result from the inhibition of HSP kinases, followed by the downregulation of HSP-70 and HSP-90 protein expression
HSP90↓,
MDM2↓, (MDM2), an onco-protein that promotes p53 destruction, can be inhibited by quercetin
RAS↓, quercetin can prevent Ras proteins from being expressed. In one study, quercetin was found to inhibit the expression of Harvey rat sarcoma (H-Ras), K-Ras, and neuroblastoma rat sarcoma (N-Ras) in human breast cancer cells,
eff↑, there was a substantial difference in EMT markers such as vimentin, N-cadherin, Snail, Slug, Twist, and E-cadherin protein expression in response to AuNPs-Qu-5, inhibiting the migration and invasion of MCF-7 and MDA-MB cells

3369-

QC,

Pharmacological basis and new insights of quercetin action in respect to its anti-cancer effects

Review,

Pca,

FAK↓, Quercetin can inhibit HGF-induced melanoma cell migration by inhibiting the activation of c-Met and its downstream Gabl, FAK and PAK [84]
TumCCA↑, stimulation of cell cycle arrest at the G1 stage
p‑pRB↓, mediated through regulation of p21 CDK inhibitor and suppression of pRb phosphorylation resulting in E2F1 sequestering.
CDK2↑, low dose of quercetin has brought minor DNA injury and Chk2 induction
CycB/CCNB1↓, quercetin has a role in the reduction of cyclin B1 and CDK1 levels,
CDK1↓,
EMT↓, quercetin suppresses epithelial to mesenchymal transition (EMT) and cell proliferation through modulation of Sonic Hedgehog signaling pathway
PI3K↓, quercetin on other pathways such as PI3K, MAPK and WNT pathways have also been validated in cervical cancer
MAPK↓,
Wnt↓,
ROS↑, colorectal cancer, quercetin has been shown to suppress carcinogenesis through various mechanisms including affecting cell proliferation, production of reactive oxygen species and expression of miR-21
miR-21↑,
Akt↓, Figure 1 anti-cancer mechanisms
NF-kB↓,
FasL↑,
Bak↑,
BAX↑,
Bcl-2↓,
Casp3↓,
Casp9↑,
P53↑,
p38↑,
MAPK↑,
Cyt‑c↑,
PARP↓,
CHOP↑,
ROS↓,
LDH↑,
GRP78/BiP↑,
ERK↑,
MDA↓,
SOD↑,
GSH↑,
NRF2↑,
VEGF↓,
PDGF↓,
EGF↓,
FGF↓,
TNF-α↓,
TGF-β↓,
VEGFR2↓,
EGFR↓,
FGFR1↓,
mTOR↓,
cMyc↓,
MMPs↓,
LC3B-II↑,
Beclin-1↑,
IL1β↓,
CRP↓,
IL10↓,
COX2↓,
IL6↓,
TLR4↓,
Shh↓,
HER2/EBBR2↓,
NOTCH↓,
DR5↑, quercetin has enhanced DR5 expression in prostate cancer cells
HSP70/HSPA5↓, Quercetin has also suppressed the upsurge of hsp70 expression in prostate cancer cells following heat treatment and enhanced the quantity of subG1 cells
CSCs↓, Quercetin could also suppress cancer stem cell attributes and metastatic aptitude of isolated prostate cancer cells through modulating JNK signaling pathway
angioG↓, Quercetin inhibits angiogenesis-mediated of human prostate cancer cells through negatively modulating angiogenic factors (TGF-β, VEGF, PDGF, EGF, bFGF, Ang-1, Ang-2, MMP-2, and MMP-9)
MMP2↓,
MMP9↓,
IGFBP3↑, Quercetin via increasing the level of IGFBP-3 could induce apoptosis in PC-3 cells
uPA↓, Quercetin through decreasing uPA and uPAR expression and suppressing cell survival protein and Ras/Raf signaling molecules could decrease prostate cancer progression
uPAR↓,
RAS↓,
Raf↓,
TSP-1↑, Quercetin through TSP-1 enhancement could effectively inhibit angiogenesis

3372-

QC,

FIS,

KaempF,

Anticancer Potential of Selected Flavonols: Fisetin, Kaempferol, and Quercetin on Head and Neck Cancers

Review,

HNSCC,

ROCK1↑, quercetin affects the level of RhoA and NF-κB proteins in SAS cells, and stimulates the expression of RhoA, ROCK1, and NF-κB in SAS cells [53].
TumCCA↓, inhibition of the cell cycle;
HSPs↓, inhibition of heat shock proteins;
RAS↓, inhibition of Ras protein expression.
ROS↑, fisetin induces production of reactive oxygen species (ROS), increases Ca2+ release, and decreases the mitochondrial membrane potential (Ψm) in head and neck neoplastic cells.
Ca+2↑,
MMP↓,
Cyt‑c↑, quercetin increases the expression level of cytochrome c, apoptosis inducing factor and endonuclease G
Endon↑,
MMP9↓, quercetin inhibits MMP-9 and MMP-2 expression and reduces levels of the following proteins: MMP-2, -7, -9 [49,53] and -10
MMP2↓,
MMP7↓,
MMP-10↓,
VEGF↓, as well as VEGF, NF-κB p65, iNOS, COX-2, and uPA, PI3K, IKB-α, IKB-α/β, p-IKKα/β, FAK, SOS1, GRB2, MEKK3 and MEKK7, ERK1/2, p-ERK1/2, JNK1/2, p38, p-p38, c-JUN, and pc-JUN
NF-kB↓,
p65↓,
iNOS↓,
COX2↓,
uPA↓,
PI3K↓,
FAK↓,
MEK↓,
ERK↓,
JNK↓,
p38↓,
cJun↓,
FOXO3↑, Quercetin causes an increase in the level of FOXO1 protein both in a dose- and time-dependent way; however, it does not affect changes in expression of FOXO3a

3083-

RES,

Resveratrol suppresses breast cancer cell invasion by inactivating a RhoA/YAP signaling axis

in-vitro,

BC,

MDA-MB-231

in-vitro,

BC,

MDA-MB-468

YAP/TEAD↓, we demonstrate that resveratrol decreases the expression of YAP target genes
Rho↓, Strikingly, we also demonstrate that resveratrol inactivates RhoA, leading to the activation of Lats1 and induction of YAP phosphorylation.
FAK↓, REV decreases breast cancer cell invasion by inhibiting FAK,44 Rac and Cdc4245 activities
MMP9↓, REV has been shown to downregulate MMP-9 expression
ChemoSen↑, REV enhances the anticancer effects of doxorubicin in breast cancer cells
RAS↓, we reported that REV suppresses LPA-induced EGF receptor activation and subsequent inhibition a Ras/RhoA/ROCK signaling in ovarian cancer cells
ROCK1↓,
TumCI↓, REV may be used to reduce invasion and metastasis of breast cancer cells to improve outcomes for this devastating disease.
TumMeta↓,

2127-

TQ,

Therapeutic Potential of Thymoquinone in Glioblastoma Treatment: Targeting Major Gliomagenesis Signaling Pathways

Review,

GBM,

chemoP↑, TQ can specifically sensitize tumor cells towards conventional cancer treatments and minimize therapy-associated toxic effects in normal cells
ChemoSen↑,
BioAv↑, TQ adds another advantage in overcoming blood-brain barrier
PTEN↑, TQ upregulates PTEN signaling [72, 73], interferes with PI3K/Akt signaling and promotes G(1) arrest, downregulates PI3K/Akt
PI3K↓,
Akt↓,
TumCCA↓,
NF-kB↓, and NF-κB and their regulated gene products, such as p-AKT, p65, XIAP, Bcl-2, COX-2, and VEGF, and attenuates mTOR activity
p‑Akt↓,
p65↓,
XIAP↓,
Bcl-2↓,
COX2↓,
VEGF↓,
mTOR↓,
RAS↓, Studies in colorectal cancer have demonstrated that TQ inhibits the Ras/Raf/MEK/ERK signaling
Raf↓,
MEK↓,
ERK↓,
MMP2↓, Multiple studies have reported that TQ downregulates FAC and reduces the secretion of MMP-2 and MMP-9 and thereby reduces GBM cells migration, adhesion, and invasion
MMP9↓,
TumCMig↓,
TumCI↓,
Casp↑, caspase activation and PARP cleavage
cl‑PARP↑,
ROS⇅, TQ is hypothesized to act as an antoxidant at lower concentrations and a prooxidant at higher concentrations depending on its environment [89]
ROS↑, In tumor cells specifically, TQ generates ROS production that leads to reduced expression of prosurvival genes, loss of mitochondrial potential,
MMP↓,
eff↑, elevated level of ROS generation and simultaneous DNA damage when treated with a combination of TQ and artemisinin
Telomerase↓, inhibition of telomerase by TQ through the formation of G-quadruplex DNA stabilizer, subsequently leads to rapid DNA damage which can eventually induce apoptosis in cancer cells specifically
DNAdam↑,
Apoptosis↑,
STAT3↓, TQ has shown to suppress STAT3 in myeloma, gastric, and colon cancer [86, 171, 172]
RadioS↑, TQ might enhance radiation therapeutic benefit by enhancing the cytotoxic efficacy of radiation through modulation of cell cycle and apoptosis [31]

4837-

Uro,

Urolithins: The Gut Based Polyphenol Metabolites of Ellagitannins in Cancer Prevention, a Review

Review,

Var,

AntiCan↑, anticancer compounds that can mediate their cancer-preventive activities through cell cycle arrest, aromatase inhibition, induction of apoptosis, tumor suppression, promotion of autophagy, and senescence, transcriptional regulation of oncogenes, and
TumCCA↑,
Apoptosis↑,
TumAuto↑,
*BioAv↝, The ellagic acid then undergoes series of transformations by the gut microbiota forming different urolithin molecules.
*BioAv↑, Urolithins have been reported to exhibit good bioavailability compared to ET and EA, and they are detected in concentrations at a micromolar range in plasma and urine samples
RAS↓, figure 2
ERK↓,
AR↓,
TumCP↓,
PI3K↓,
Akt↓,
NF-kB↓,
COX2↓,
IL6↓,
IL1β↓,
Wnt↓,
β-catenin/ZEB1↓,
cMyc↓,
P53↑,
Casp3↑,
PARP↑, Uro-A (35 μM) treatment of prostate cancer cell lines, PC-3 and C4-2B, resulted in cell growth arrest and induction of apoptosis with the activation of caspase-3 and PARP.
ROS↓, The urolithins mechanism of action involves decreased oxidative stress, cell cycle arrest, inhibition of survival pathways, induction of apoptosis
toxicity↓, A a favorable review in its generally safe (GRAS) notification program, and 1,000 mg/serving of urolithin A can be used as a functional food ingredient

1817-

VitK2,

Research progress on the anticancer effects of vitamin K2

Review,

Var,

TumCCA↑, involving cell-cycle arrest
Apoptosis↑, apoptosis, autophagy and invasion
TumAuto↑,
TumCI↓,
TumCG↓, inhibit the growth of cancer cells
ChemoSen↓, combination treatment of VK2 and established chemotherapeutics may achieve better results, with fewer side effects
ChemoSideEff↓,
toxicity∅, VK2 is milder, but causes no side effects, whereas VK1 has the least strong function
eff↑, combination of VK2 and vitamin E suppressed the growth of the primary tumor and obliterated the intraperitoneal dissemination in a 65-year-old man with ruptured HCC
cycD1/CCND1↓, decreases in cyclin D1 and cyclin-dependent kinase 4 (CDK4) levels
CDK4↓,
eff↑, pretreatment with VK2 prior to sorafenib treatment is proven to exert more effective HCC growth inhibition in animals than treatment with either alone
IKKα↓, VK2 can inhibit the IκB kinase (IKK)/IκB/NF-κB pathway
NF-kB↓,
other↑, stimulate the phosphorylation of PKA and activate activating protein 2 (AP-2)
p27↑, VK2 upregulates the expression of p27
cMyc↓, 5 µΜ VK2 exposure inhibited c-MYC expression in HL-60 leukemia cells
i-ROS↑, VK2 treatment increased the intracellular level of the reactive oxygen species (ROS)
Bcl-2↓, VK2 decreases Bcl-2 expression and increases the expression of Bcl-2-associated X protein (Bax)
BAX↑,
p38↑, VK2 activates p38 MAPK to its phosphorylated form
MMP↓, mitochondrial membrane potential was depolarized and caspase-9 was activated
Casp9↑,
p‑ERK↓, VK2 is reported to inhibit ERK phosphorylation by suppressing Ras activation
RAS↓,
MAPK↓, subsequently suppressing the activation of MAPK kinase (MEK)
p‑P53↑, VK2 stimulated the extrinsic apoptosis pathway by increasing p53 phosphorylation
Casp8↑, caspase-8 activation and further activates caspase-3
Casp3↑,
cJun↑, increasing the expression of c-JUN and c-MYC;
MMPs↓, downregulating the expression of matrix metalloproteinases (MMPs)
eff↑, combination of VK2 with other chemotherapy agents can produce stronger effects than the use of either alone
eff↑, combination of vitamin D3 with VK2 on cancer cells can synergistically improve the induction of cellular differentiation and also significantly reduces the risk of hypercalcemia and vascular calcification

Showing Research Papers: 1 to 27 of 27

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 27

Pathway results for Effect on Cancer / Diseased Cells:

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

antiOx↑, 7, Catalase↑, 3, GPx↑, 1, GSH↑, 2, HO-1↑, 2, Keap1↑, 1, lipid-P↓, 1, Nrf1↑, 1, NRF2↑, 4, ROS↓, 4, SIRT3↑, 1, SOD↑, 2,

Metal & Cofactor Biology ⓘ

IronCh↑, 2,

Mitochondria & Bioenergetics ⓘ

ATP↑, 1, PGC-1α↑, 2,

Core Metabolism/Glycolysis ⓘ

PPARα↑, 1, PPARγ↑, 1, SIRT1↑, 1,

Cell Death ⓘ

Akt↓, 1, Casp3↓, 1, MAPK↓, 1,

Proliferation, Differentiation & Cell State ⓘ

ERK↓, 1, GSK‐3β↓, 1, PI3K↓, 1, RAS↓, 1,

Migration ⓘ

AntiAg↑, 1, Rho↓, 1,

Angiogenesis & Vasculature ⓘ

angioG↓, 1,

Barriers & Transport ⓘ

BBB↑, 1,

Immune & Inflammatory Signaling ⓘ

COX2↓, 2, IL10↓, 1, IL17↓, 1, IL1β↓, 1, Inflam↓, 3, MCP1↓, 1, NF-kB↓, 2, TNF-α↓, 2,

Synaptic & Neurotransmission ⓘ

EndoR↑, 1, monoA↑, 1, tau↓, 1,

Protein Aggregation ⓘ

Aβ↓, 2,

Hormonal & Nuclear Receptors ⓘ

testos↑, 1,

Drug Metabolism & Resistance ⓘ

BioAv↓, 4, BioAv↑, 2, BioAv↝, 1, BioEnh↑, 1, Half-Life↑, 1,

Clinical Biomarkers ⓘ

BP↓, 1,

Functional Outcomes ⓘ

cardioP↑, 2, memory↑, 1, neuroP↑, 2, Pain↓, 1, toxicity↓, 1,
Total Targets: 53

Scientific Paper Hit Count for: RAS, RAS

5 Quercetin
3 Honokiol
2 Curcumin
2 diet FMD Fasting Mimicking Diet
2 Fisetin
1 Atorvastatin
1 Berberine
1 Betulinic acid
1 Carvacrol
1 EGCG (Epigallocatechin Gallate)
1 Piperine
1 Exercise
1 Luteolin
1 Naringin
1 Niclosamide (Niclocide)
1 Phenethyl isothiocyanate
1 Piperlongumine
1 Kaempferol
1 Resveratrol
1 Thymoquinone
1 Urolithin
1 Vitamin K2

Query results interpretion may depend on "conditions" listed in the research papers.
Such Conditions may include : 
  -low or high Dose
  -format for product, such as nano of lipid formations
  -different cell line effects
  -synergies with other products 
  -if effect was for normal or cancerous cells

Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:%  Target#:269  State#:%  Dir#:1
  wNotes=on  sortOrder:rid,rpid

RAS Cancer Research Results

Pathway results for Effect on Cancer / Diseased Cells:

Redox & Oxidative Stress ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Kinase & Signal Transduction ⓘ

Transcription & Epigenetics ⓘ

Protein Folding & ER Stress ⓘ

Autophagy & Lysosomes ⓘ

DNA Damage & Repair ⓘ

Cell Cycle & Senescence ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Barriers & Transport ⓘ

Immune & Inflammatory Signaling ⓘ

Protein Aggregation ⓘ

Hormonal & Nuclear Receptors ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

Metal & Cofactor Biology ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Barriers & Transport ⓘ

Immune & Inflammatory Signaling ⓘ

Synaptic & Neurotransmission ⓘ

Protein Aggregation ⓘ

Hormonal & Nuclear Receptors ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

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