cycE/CCNE Cancer Research Results
cycE/CCNE, Cyclin E: Click to Expand ⟱
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Cyclin E regulates multiple downstream molecules, such as the retinoblastoma susceptibility gene (RB1) and the transcription factor E2F.
Cyclin E (Cyclin E1 and Cyclin E2) is the key regulator of the late G1 → S-phase transition.
Cyclin E is a prognostic marker in breast cancer, its altered expression increased with the increasing stage and grade of the tumor.
Cyclin E is a regulatory protein that plays a critical role in the cell cycle, particularly in the transition from the G1 phase to the S phase. Its expression levels can significantly influence cancer progression and patient prognosis.
Cyclin E expression is frequently elevated in various cancers and is generally associated with poor prognosis. Its role in promoting cell cycle progression makes it a potential biomarker for tumor aggressiveness and patient outcomes.
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Scientific Papers found: Click to Expand⟱
Apoptosis↑, induction of apoptosis, inhibition of proliferation, and disruption of cancer cell signaling pathways, including the MAPK, PI3K/AKT, and NF-κB pathways.
TumCP↓,
MAPK↓,
PI3K↓,
Akt↓,
NF-kB↓,
AntiCan↑, Allicin and its other derivatives, such as diallyl disulfide (DADS) and ajoene, have been found to have strong anticancer potential both in vitro and in vivo.
ChemoSen↑, effectiveness of allicin in augmenting conventional chemotherapy and retarding tumor growth proves that allicin is one of the most efficient complementary therapies.
TumCCA↑, In liver cancer, allicin has been shown to mediate cell cycle arrest and apoptosis
Apoptosis↑,
BioAv↑, Allicin (diallyl thiosulfinate) is a compound that is generated when a garlic clove is crushed
selectivity↑, Furthermore, it has no influence on the growth of healthy intestinal cells when it causes stomach cancer cells to undergo apoptosis
TGF-β↓, Allicin can reduce the production of TGF-β2 and its receptor after directly entering gastric cancer cells.
ROS↑, It induces oxidative stress by generating reactive oxygen species (ROS), leading to DNA damage and activation of key apoptotic mediators such as phospho-p53 and p21 [81].
DNAdam↑,
p‑P53↑,
P21↑,
cycD1/CCND1↓, Additionally, cyclin D1, cyclin E, and cyclin-dependent kinases (CDKs) can all be inhibited by allicin.
cycE/CCNE↓,
CDK4↓, suppressing the CDK-4/6/cyclin D complex
CDK6↓,
MMP↓, By lowering the outer mitochondrial membrane potential (MMP), allicin raises levels of nuclear factor kappa B (NF-κB), the proapoptotic protein Bax, while decreasing the antiapoptotic protein Bcl-2, which leads to apoptosis.
NF-kB↑,
BAX↑,
Bcl-2↓,
ER Stress↑, cellular effects of allicin, including its role in inducing ER stress
Casp↑, enhancing caspase activation and apoptosis-inducing factor (AIF)-mediated cell death.
AIF↑,
Fas↑, increasing Fas receptor expression and its binding to Fas ligand (FasL), leading to apoptosis through caspase-8 and cytochrome c activation.
Casp8↑,
Cyt‑c↑,
cl‑PARP↑, leading to poly (ADP-ribose) polymerase (PARP) cleavage and DNA fragmentation.
Ca+2↑, allicin elevates intracellular free Ca2⁺ levels, causing endoplasmic reticulum (ER) stress, which plays a critical role in apoptosis induction
*NRF2↑, by activating the Nrf2 pathway via KLF9, allicin protects against arsenic trioxide-induced liver damage,
*chemoP↑, Additionally, allicin has shown promise in reducing hepatotoxicity caused by tamoxifen (TAM), a commonly used treatment for hormone-dependent breast cancer
*GutMicro↑, Shi et al. [85] found that allicin can ameliorate high-fat diet-induced obesity in mice by altering their gut microbiome.
CycB/CCNB1↑, DATS impaired cell survival in the G2 phase by significantly upregulating cyclins A2 and B1.
H2S↑, DATS can also react with the cellular thiol glutathione to create H2S gas, which can control several other cellular functions [79].
HIF-1↓, allicin treatment (40 µg/ml) for NSCLC lowers the expression of HIF-1 and HIF-2 in hypoxic cells [73]
RadioS↑, Allicin has been shown to increase the sensitivity of X-ray radiation therapy in colorectal cancer, presumably by suppressing the levels of NF-κB, IKKβ mRNA, p-NF-κB, and p-IKKβ protein expression in vitro and in vivo
TGF-β↓, Allicin can reduce the expression of TGF-2 and its receptor after entering directly into gastric cancer cell
cycD1/CCND1↓, followed by not only downexpression of cyclinD1, cyclinE, and cyclin-dependent kinase (CDK),
cycE/CCNE↓,
CDK1↓, cyclin-dependent kinase (CDK)
DNAdam↑, but also causing DNA damage and generating ROS
ROS↑,
BAX↑, Allicin increases the levels of Bax (proapoptotic protein), Bcl-2 (antiapoptotic protein), and JNK
JNK↑,
MMP↓, through reduction in outer mitochondrial membrane potential
p38↑, allicin induces p38 mitogen that could induce the protein kinase (MAPK) and then increase the expression of Fas binding to Fas ligand (Fas L) and finally activate death pathway through activation of cyt C and caspase-8.
MAPK↑,
Fas↑,
Cyt‑c↑,
Casp8↑,
PARP↑, allicin makes caspase-dependent apoptosis through elevating PARP, caspase-3 and caspase-9, which are mediated by enhanced discharging of mitochondria cyt C to the cytosol.
Casp3↑,
Casp9↑,
Ca+2↑, allicin induces apoptosis via increasing the amounts of free Ca2+, ER stress.
ER Stress↑,
P21↑, generating ROS to produce p21 and phospho-p53 (Ser15).
CDK2↓, Then p21 suppressed the CDK-4/6/cyclinD complex, P21-PCNA, P21-CDK2, and subsequently reduced cdk1/cyclinB1 complex for G2/M phase cell cycle arrest
CDK6↑,
TumCCA↑,
CDK4↓, Then p21 suppressed the CDK-4/6/cyclinD complex
TumCP↓,
TumCCA↑,
Apoptosis↑,
STAT3↓,
Akt↓,
P21↑,
BAX↑,
cycD1/CCND1↓,
cycE/CCNE↓,
survivin↓,
XIAP↓,
Bcl-2↓,
eff↑, ANDRO combined with gemcitabine significantly induce stronger cell cycle arrest and more obvious apoptosis than each single treatment.
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TumCCA↑, G2/M cell cycle arrest.
cycD1/CCND1↓,
cycE/CCNE↓,
CDK1/2/5/9∅, CDK1
PSA↓,
cycD1/CCND1↓, cyclinD1 and cyclinD2
cycE/CCNE↓,
CDK2↓,
CDK4/6↓,
P21↑,
AR↓,
TumCP↓, DHA exerts anticancer effects through various molecular mechanisms, such as inhibiting proliferation, inducing apoptosis, inhibiting tumor metastasis and angiogenesis, promoting immune function, inducing autophagy and endoplasmic reticulum (ER) stres
Apoptosis↑,
TumMeta↓,
angioG↓,
TumAuto↑,
ER Stress↑,
ROS↑, DHA could increase the level of ROS in cells, thereby exerting a cytotoxic effect in cancer cells
Ca+2↑, activation of Ca2+ and p38 was also observed in DHA-induced apoptosis of PC14 lung cancer cells
p38↑,
HSP70/HSPA5↓, down-regulation of heat-shock protein 70 (HSP70) might participate in the apoptosis of PC3 prostate cancer cells induced by DHA
PPARγ↑, DHA inhibited the growth of colon tumor by inducing apoptosis and increasing the expression of peroxisome proliferator-activated receptor γ (PPARγ)
GLUT1↓, DHA was shown to inhibit the activity of glucose transporter-1 (GLUT1) and glycolytic pathway by inhibiting phosphatidyl-inositol-3-kinase (PI3K)/AKT pathway and downregulating the expression of hypoxia inducible factor-1α (HIF-1α)
Glycolysis↓, Inhibited glycolysis
PI3K↓,
Akt↓,
Hif1a↓,
PKM2↓, DHA could inhibit the expression of PKM2 as well as inhibit lactic acid production and glucose uptake, thereby promoting the apoptosis of esophageal cancer cells
lactateProd↓,
GlucoseCon↓,
EMT↓, regulating the EMT-related genes (Slug, ZEB1, ZEB2 and Twist)
Slug↓, Downregulated Slug, ZEB1, ZEB2 and Twist in mRNA level
Zeb1↓,
ZEB2↓,
Twist↓,
Snail?, downregulated the expression of Snail and PI3K/AKT signaling pathway, thereby inhibiting metastasis
CAFs/TAFs↓, DHA suppressed the activation of cancer-associated fibroblasts (CAFs) and mouse cancer-associated fibroblasts (L-929-CAFs) by inhibiting transforming growth factor-β (TGF-β signaling
TGF-β↓,
p‑STAT3↓, blocking the phosphorylation of STAT3 and polarization of M2 macrophages
M2 MC↓,
uPA↓, DHA could inhibit the growth and migration of breast cancer cells by inhibiting the expression of uPA
HH↓, via inhibiting the hedgehog signaling pathway
AXL↓, DHA acted as an Axl inhibitor in prostate cancer, blocking the expression of Axl through the miR-34a/miR-7/JARID2 pathway, thereby inhibiting the proliferation, migration and invasion of prostate cancer cells.
VEGFR2/KDR/Flk1↓, inhibition of VEGFR2-mediated angiogenesis
JNK↑, JNK pathway activated and Beclin 1 expression upregulated.
Beclin-1↑,
GRP78/BiP↑, Glucose regulatory protein 78 (GRP78, an ER stress-related molecule) was upregulated after DHA treatment.
eff↑, results demonstrated that DHA-induced ER stress required iron
eff↑, DHA was used in combination with PDGFRα inhibitors (sunitinib and sorafenib), it could sensitize ovarian cancer cells to PDGFR inhibitors and achieved effective therapeutic efficacy
eff↑, DHA combined with 2DG (a glycolysis inhibitor) synergistically induced apoptosis through both exogenous and endogenous apoptotic pathways
eff↑, histone deacetylase inhibitors (HDACis) enhanced the anti-tumor effect of DHA by inducing apoptosis.
eff↑, DHA enhanced PDT-induced cell growth inhibition and apoptosis, increased the sensitivity of esophageal cancer cells to PDT by inhibiting the NF-κB/HIF-1α/VEGF pathway
eff↑, DHA was added to magnetic nanoparticles (MNP), and the MNP-DHA has shown an effect in the treatment of intractable breast cancer
IL4↓, downregulated IL-4;
DR5↑, Upregulated DR5 in protein, Increased DR5 promoter activity
Cyt‑c↑, Released cytochrome c from the mitochondria to the cytosol
Fas↑, Upregulated fas, FADD, Bax, cleaved-PARP
FADD↑,
cl‑PARP↑,
cycE/CCNE↓, Downregulated Bcl-2, Bcl-xL, procaspase-3, Cyclin E, CDK2 and CDK4
CDK2↓,
CDK4↓,
Mcl-1↓, Downregulated Mcl-1
Ki-67↓, Downregulated Ki-67 and Bcl-2
Bcl-2↓,
CDK6↓, Downregulated of Cyclin E, CDK2, CDK4 and CDK6
VEGF↓, Downregulated VEGF, COX-2 and MMP-9
COX2/PTGS2↓,
MMP9↓,
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/CCNB1↓,
NF-kB↓,
cycD1/CCND1↓, decreased cyclin D, E, CDK2-4, E2F1 Increased Cip 1/p21, Kip 1/p27
cycE/CCNE↓,
E2Fs↓,
P21↑,
p27/CDKN1B↑,
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/PTGS2↓,
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↑,
TumCCA↑, withaferin A suppressed cell proliferation in prostate, ovarian, breast, gastric, leukemic, and melanoma cancer cells and osteosarcomas by stimulating the inhibition of the cell cycle at several stages, including G0/G1 [86], G2, and M phase
H3↑, via the upregulation of phosphorylated Aurora B, H3, p21, and Wee-1, and the downregulation of A2, B1, and E2 cyclins, Cdc2 (Tyr15), phosphorylated Chk1, and Chk2 in DU-145 and PC-3 prostate cancer cells.
P21↑,
cycA1/CCNA1↓,
CycB/CCNB1↓,
cycE/CCNE↓,
CDC2↓,
CHK1↓,
Chk2↓,
p38↑, nitiated cell death in the leukemia cells by increasing the expression of p38 mitogen-activated protein kinases (MAPK)
MAPK↑,
E6↓, educed the expression of human papillomavirus E6/E7 oncogenes in cervical cancer cells
E7↓,
P53↑, restored the p53 pathway causing the apoptosis of cervical cancer cells.
Akt↓, oral dose of 3–5 mg/kg withaferin A attenuated the activation of Akt and stimulated Forkhead Box-O3a (FOXO3a)-mediated prostate apoptotic response-4 (Par-4) activation,
FOXO3↑,
ROS↑, the generation of reactive oxygen species, histone H2AX phosphorylation, and mitochondrial membrane depolarization, indicating that withaferin A can cause the oxidative stress-mediated killing of oral cancer cells [
γH2AX↑,
MMP↓,
mitResp↓, withaferin A inhibited the expansion of MCF-7 and MDA-MB-231 human breast cancer cells by ROS production, owing to mitochondrial respiration inhibition
eff↑, combination treatment of withaferin A and hyperthermia induced the death of HeLa cells via a decrease in the mitochondrial transmembrane potential and the downregulation of the antiapoptotic protein myeloid-cell leukemia 1 (MCL-1)
TumCD↑,
Mcl-1↓,
ER Stress↑, . Withaferin A also attenuated the development of glioblastoma multiforme (GBM), both in vitro and in vivo, by inducing endoplasmic reticulum stress via activating the transcription factor 4-ATF3-C/EBP homologous protein (ATF4-ATF3-CHOP)
ATF4↑,
ATF3↑,
CHOP/DDIT3↑,
NOTCH↓, modulating the Notch-1 signaling pathway and the downregulation of Akt/NF-κB/Bcl-2 . withaferin A inhibited the Notch signaling pathway
NF-kB↓,
Bcl-2↓,
STAT3↓, Withaferin A also constitutively inhibited interleukin-6-induced phosphorylation of STAT3,
CDK1↓, lowering the levels of cyclin-dependent Cdk1, Cdc25C, and Cdc25B proteins,
β-catenin/ZEB1↓, downregulation of p-Akt expression, β-catenin, N-cadherin and epithelial to the mesenchymal transition (EMT) markers
N-cadherin↓,
EMT↓,
Cyt‑c↑, depolarization and production of ROS, which led to the release of cytochrome c into the cytosol,
eff↑, combinatorial effect of withaferin A and sulforaphane was also observed in MDA-MB-231 and MCF-7 breast cancer cells, with a dramatic reduction of the expression of the antiapoptotic protein Bcl-2 and an increase in the pro-apoptotic Bax level, thus p
CDK4↓, downregulates the levels of cyclin D1, CDK4, and pRB, and upregulates the levels of E2F mRNA and tumor suppressor p21, independently of p53
p‑RB1↓,
PARP↑, upregulation of Bax and cytochrome c, downregulation of Bcl-2, and activation of PARP, caspase-3, and caspase-9 cleavage
cl‑Casp3↑,
cl‑Casp9↑,
NRF2↑, withaferin A binding with Keap1 causes an increase in the nuclear factor erythroid 2-related factor 2 (Nrf2) protein levels, which in turn, regulates the expression of antioxidant proteins that can protect the cells from oxidative stress.
ER-α36↓, Decreased ER-α
LDHA↓, inhibited growth, LDHA activity, and apoptotic induction
lipid-P↑, induction of oxidative stress, increased lipid peroxidation,
AP-1↓, anti-inflammatory qualities of withaferin A are specifically attributed to its inhibition of pro-inflammatory molecules, α-2 macroglobulin, NF-κB, activator protein 1 (AP-1), and cyclooxygenase-2 (COX-2) inhibition,
COX2/PTGS2↓,
RenoP↑, showing strong evidence of the renoprotective potential of withaferin A due to its anti-inflammatory activity
PDGFR-BB↓, attenuating the BB-(PDGF-BB) platelet growth factor
SIRT3↑, by increasing the sirtuin3 (SIRT3) expression
MMP2↓, withaferin A inhibits matrix metalloproteinase-2 (MMP-2) and MMP-9,
MMP9↓,
NADPH↑, but also provokes mRNA stimulation for a set of antioxidant genes, such as NADPH quinone dehydrogenase 1 (NQO1), glutathione-disulfide reductase (GSR), Nrf2, heme oxygenase 1 (HMOX1),
NQO1↑,
GSR↑,
HO-1↑,
*SOD2↑, cardiac ischemia-reperfusion injury model. Withaferin A triggered the upregulation of superoxide dismutase SOD2, SOD3, and peroxiredoxin 1(Prdx-1).
*Prx↑,
*Casp3?, and ameliorated cardiomyocyte caspase-3 activity
eff↑, combination with doxorubicin (DOX), is also responsible for the excessive generation of ROS
Snail↓, inhibition of EMT markers, such as Snail, Slug, β-catenin, and vimentin.
Slug↓,
Vim↓,
CSCs↓, highly effective in eliminating cancer stem cells (CSC) that expressed cell surface markers, such as CD24, CD34, CD44, CD117, and Oct4 while downregulating Notch1, Hes1, and Hey1 genes;
HEY1↓,
MMPs↓, downregulate the expression of MMPs and VEGF, as well as reduce vimentin, N-cadherin cytoskeleton proteins,
VEGF↓,
uPA↓, and protease u-PA involved in the cancer cell metastasis
*toxicity↓, A was orally administered to Wistar rats at a dose of 2000 mg/kg/day and had no adverse effects on the animals
CDK2↓, downregulated the activation of Bcl-2, CDK2, and cyclin D1
CDK4↓, Another study also demonstrated the inhibition of Hsp90 by withaferin A in a pancreatic cancer cell line through the degradation of Akt, cyclin-dependent kinase 4 Cdk4,
HSP90↓,
*Inflam↓, BBR exerts remarkable anti-inflammatory (94–96), antiviral (97), antioxidant (98), antidiabetic (99), immunosuppressive (100), cardiovascular (101, 102), and neuroprotective (103) activities.
*antiOx↑,
*cardioP↑,
*neuroP↑,
TumCCA↑, BBR could induce G1 cycle arrest in A549 lung cancer cells by decreasing the levels of cyclin D1 and cyclin E1
cycD1/CCND1↓,
cycE/CCNE↓,
CDC2↓, BBR also induced G1 cycle arrest by inhibiting cyclin B1 expression and CDC2 kinase in some cancer cells
AMPK↝, BBR has been suggested to induce autophagy in glioblastoma by targeting the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR)/ULK1 pathway
mTOR↝,
Casp8↑, BBR has been revealed to stimulate apoptosis in leukemia by upregulation of caspase-8 and caspase-9
Casp9↑,
Cyt‑c↑, in skin squamous cell carcinoma A431 cells by increasing cytochrome C levels
TumCMig↓, BBR has been confirmed to inhibit cell migration and invasion by inhibiting the expression of epithelial–mesenchymal transition (EMT)
TumCI↓,
EMT↓,
MMPs↓, metastasis-related proteins, such as matrix metalloproteinases (MMPs) and E-cadherin,
E-cadherin↓,
Telomerase↓, BBR has shown antitumor effects by interacting with microRNAs (125) and inhibiting telomerase activity
*toxicity↓, Numerous studies have revealed that BBR is a safe and effective treatment for CRC
GRP78/BiP↓, Downregulates GRP78
EGFR↓, Downregulates EGFR
CDK4↓, downregulates CDK4, TERT, and TERC
COX2/PTGS2↓, Reduces levels of COX-2/PGE2, phosphorylation of JAK2 and STAT3, and expression of MMP-2/-9.
PGE2↓,
p‑JAK2↓,
p‑STAT3↓,
MMP2↓,
MMP9↓,
GutMicro↑, BBR can inhibit tumor growth through meditation of the intestinal flora and mucosal barrier, and generally and ultimately improve weight loss. BBR has been reported to modulate the composition of intestinal flora and significantly reduce flora divers
eff↝, BBR can regulate the activity of P-glycoprotein (P-gp), and potential drug-drug interactions (DDIs) are observed when BBR is coadministered with P-gp substrates
*BioAv↓, the efficiency of BBR is limited by its low bioavailability due to its poor absorption rate in the gut, low solubility in water, and fast metabolism. Studies have shown that the oral bioavailability of BBR is 0.68% in rats
BioAv↑, combining it with p-gp inhibitors (such as tariquidar and tetrandrine) (196, 198), and modification to berberine organic acid salts (BOAs)
Inflam↓, BBR has documented to have anti-diabetic, anti-inflammatory and anti-microbial (both anti-bacterial and anti-fungal) properties.
IL6↓, BBRs can inhibit IL-6, TNF-alpha, monocyte chemo-attractant protein 1 (MCP1) and COX-2 production and expression.
MCP1/CCL2↓,
COX2/PTGS2↓,
PGE2↓, BBRs can also effect prostaglandin E2 (PGE2)
MMP2↓, and decrease the expression of key genes involved in metastasis including: MMP2 and MMP9.
MMP9↓,
DNAdam↑, BBR induces double strand DNA breaks and has similar effects as ionizing radiation
eff↝, In some cell types, this response has been reported to be TP53-dependent
Telomerase↓, This positively-charged nitrogen may result in the strong complex formations between BBR and nucleic acids and induce telomerase inhibition and topoisomerase poisoning
Bcl-2↓, BBR have been shown to suppress BCL-2 and expression of other genes by interacting with the TATA-binding protein and the TATA-box in certain gene promoter regions
AMPK↑, BBR has been shown in some studies to localize to the mitochondria and inhibit the electron transport chain and activate AMPK.
ROS↑, targeting the activity of mTOR/S6 and the generation of ROS
MMP↓, BBR has been shown to decrease mitochondrial membrane potential and intracellular ATP levels.
ATP↓,
p‑mTORC1↓, BBR induces AMPK activation and inhibits mTORC1 phosphorylation by suppressing phosphorylation of S6K at Thr 389 and S6 at Ser 240/244
p‑S6K↓,
ERK↓, BBR also suppresses ERK activation in MIA-PaCa-2 cells in response to fetal bovine serum, insulin or neurotensin stimulation
PI3K↓, Activation of AMPK is associated with inhibition of the PI3K/PTEN/Akt/mTORC1 and Raf/MEK/ERK pathways which are associated with cellular proliferation.
PTEN↑, RES was determined to upregulate phosphatase and tensin homolog (PTEN) expression and decrease the expression of activated Akt. In HCT116 cells, PTEN inhibits Akt signaling and proliferation.
Akt↓,
Raf↓,
MEK↓,
Dose↓, The effects of low doses of BBR (300 nM) on MIA-PaCa-2 cells were determined to be dependent on AMPK as knockdown of the alpha1 and alpha2 catalytic subunits of AMPK prevented the inhibitory effects of BBR on mTORC1 and ERK activities and DNA synthes
Dose↑, In contrast, higher doses of BBR inhibited mTORC1 and ERK activities and DNA synthesis by AMPK-independent mechanisms [223,224].
selectivity↑, BBR has been shown to have minimal effects on “normal cells” but has anti-proliferative effects on cancer cells (e.g., breast, liver, CRC cells) [225–227].
TumCCA↑, BBR induces G1 phase arrest in pancreatic cancer cells, while other drugs such as gemcitabine induce S-phase arrest
eff↑, BBR was determined to enhance the effects of epirubicin (EPI) on T24 bladder cancer cells
EGFR↓, In some glioblastoma cells, BBR has been shown to inhibit EGFR signaling by suppression of the Raf/MEK/ERK pathway but not AKT signaling
Glycolysis↓, accompanied by impaired glycolytic capacity.
Dose?, The IC50 for BBR was determined to be 134 micrograms/ml.
p27/CDKN1B↑, Increased p27Kip1 and decreased CDK2, CDK4, Cyclin D and Cyclin E were observed.
CDK2↓,
CDK4↓,
cycD1/CCND1↓,
cycE/CCNE↓,
Bax:Bcl2↑, Increased BAX/BCL2 ratio was observed.
Casp3↑, The mitochondrial membrane potential was disrupted and activated caspase 3 and caspases 9 were observed
Casp9↑,
VEGFR2/KDR/Flk1↓, BBR treatment decreased VEGFR, Akt and ERK1,2 activation and the expression of MMP2 and MMP9 [235].
ChemoSen↑, BBR has been shown to increase the anti-tumor effects of tamoxifen (TAM) in both drug-sensitive MCF-7 and drug-resistant MCF-7/TAM cells.
eff↑, The combination of BBR and CUR has been shown to be effective in suppressing the growth of certain breast cancer cell lines.
eff↑, BBR has been shown to synergize with the HSP-90 inhibitor NVP-AUY922 in inducing death of human CRC.
PGE2↓, BBR inhibits COX2 and PEG2 in CRC.
JAK2↓, BBR prevented the invasion and metastasis of CRC cells via inhibiting the COX2/PGE2 and JAK2/STAT3 signaling pathways.
STAT3↓,
CXCR4↓, BBR has been observed to inhibit the expression of the chemokine receptors (CXCR4 and CCR7) at the mRNA level in esophageal cancer cells.
CCR7↓,
uPA↓, BBR has also been shown to induce plasminogen activator inhibitor-1 (PAI-1) and suppress uPA in HCC cells which suppressed their invasiveness and motility.
CSCs↓, BBR has been shown to inhibit stemness, EMT and induce neuronal differentiation in neuroblastoma cells. BBR inhibited the expression of many genes associated with neuronal differentiation
EMT↓,
Diff↓,
CD133↓, BBR also suppressed the expression of many genes associated with cancer stemness such as beta-catenin, CD133, NESTIN, N-MYC, NOTCH and SOX2
Nestin↓,
n-MYC↓,
NOTCH↓,
SOX2↓,
Hif1a↓, BBR inhibited HIF-1alpha and VEGF expression in prostate cancer cells and increased their radio-sensitivity in in vitro as well as in animal studies [290].
VEGF↓,
RadioS↑,
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TumCP↑, Here, we report that in vitro treatment of androgen-insensitive (DU145 and PC-3) and androgen-sensitive (LNCaP) prostate cancer cells with berberine inhibited cell proliferation and induced cell death in a dose-dependent (10–100 μmol/L) and time-depe
TumCCA↑, associated with G1-phase arrest, which in DU145 cells was associated with inhibition of expression of cyclins D1, D2, and E and cyclin-dependent kinase (Cdk) 2, Cdk4, and Cdk6 proteins,
cycD1/CCND1↓,
cycE/CCNE↓,
CDK2↓,
CDK4↓,
CDK6↓,
P21↑, increased expression of the Cdk inhibitory proteins (Cip1/p21 and Kip1/p27), and enhanced binding of Cdk inhibitors to Cdk.
p27/CDKN1B↑,
Apoptosis↑, Berberine also significantly (P < 0.05–0.001) enhanced apoptosis of DU145 and LNCaP cells with induction of a higher ratio of Bax/Bcl-2 proteins
Bax:Bcl2↑,
MMP↓, disruption of mitochondrial membrane potential, and activation of caspase-9, caspase-3, and poly(ADP-ribose) polymerase.
Casp9↑,
Casp3↑,
PARP↑,
DNAdam↑, analysis of DNA fragmentation
selectivity↑, Berberine Inhibits Proliferation and Viability and Induces the Death of Prostate Cancer Cells but not of Normal Prostate Epithelial Cells
Cyt‑c↑, Berberine Induces the Disruption of Mitochondrial Membrane Potential and Increases the Release of Cytochrome c
*Inflam↓, profound application as a traditional remedy for various ailments, especially inflammatory diseases including asthma, arthritis, cerebral edema, chronic pain syndrome, chronic bowel diseases, cancer
AntiCan↑,
*MAPK↑, 11-keto-BAs can stimulate Mitogen-activated protein kinases (MAPK) and mobilize the intracellular Ca(2+) that are important for the activation of human polymorphonuclear leucocytes (PMNL)
*Ca+2↝,
p‑ERK↓, AKBA prohibited the phosphorylation of extracellular signal-regulated kinase-1 and -2 (Erk-1/2) and impaired the motility of meningioma cells stimulated with platelet-derived growth factor BB
TumCI↓,
cycD1/CCND1↓, In the case of colon cancer, BA treatment on HCT-116 cells led to a decrease in cyclin D, cyclin E, and Cyclin-dependent kinases such as CDK2 and CDK4, along with significant reduction in phosphorylated Rb (pRb)
cycE/CCNE↓,
CDK2↓,
CDK4↓,
p‑RB1↓,
*NF-kB↓, convey inhibition of NF-kappaB and subsequent down-regulation of TNF-alpha expression in activated human monocytes
*TNF-α↓,
NF-kB↓, PC-3 prostate cancer cells in vitro and in vivo by inhibiting constitutively activated NF-kappaB signaling by intercepting the activity of IkappaB kinase (IKK
IKKα↓,
MCP1/CCL2↓, LPS-challenged ApoE-/- mice via inhibition of NF-κB and down regulation of MCP-1, MCP-3, IL-1alpha, MIP-2, VEGF, and TF
IL1α↓,
MIP2↓,
VEGF↓,
Tf↓,
COX2/PTGS2↓, pancreatic cancer cell lines, AKBA inhibited the constitutive expression of NF-kB and caused suppression of NF-kB regulated genes such as COX-2, MMP-9, CXCR4, and VEGF
MMP9↓,
CXCR4↓,
VEGF↓,
eff↑, AKBA and aspirin revealed that AKBA has higher potential via modulation of the Wnt/β-catenin pathway, and NF-kB/COX-2 pathway in adenomatous polyps
PPARα↓, AKBA is also responsible for down-regulation of PPAR-alpha and C/EBP-alpha in a dose and temporal dependent manner in mature adipocytes, ultimately leading to pparlipolysis
lipid-P?,
STAT3↓, activation of STAT-3 in human MM cells could be inhibited by AKBA
TOP1↓, (PKBA; a semisynthetic analogue of 11-keto-β-boswellic acid), had been reported to influence the activity of topoisomerase I & II,
TOP2↑,
5HT↓, (5-LO), responsible for catalyzing the synthesis of leukotrienes from arachidonic acid and human leucocyte elastase (HLE), and serine proteases involved in several inflammatory processes, is considered to be a potent molecular target of BA derivative
p‑PDGFR-BB↓, BA up-regulates SHP-1 with subsequent dephosphorylation of PDGFR-β and downregulation of PDGF-dependent signaling after PDGF stimulation, thereby exerting an anti-proliferative effect on HSCs hepatic stellate cells
PDGF↓,
AR↓, AKBA targets different receptors that include androgen receptor (AR), death receptor 5 (DR5), and vascular endothelial growth factor receptor 2 (VEGFR2), and leads to the inhibition of proliferation of prostate cancer cells
DR5↑, induced expression of DR4 and DR5.
angioG↓, via apoptosis induction and suppression of angiogenesis
DR4↑,
Casp3↑, AKBA resulted in activation of caspase-3 and caspase-8, and initiation of poly (ADP) ribose polymerase (PARP) cleavage.
Casp8↑,
cl‑PARP↑,
eff↑, AKBA was preincubated with LY294002 or wortmannin (inhibitors of PI3K), it caused a significant enhancement of apoptosis in HT-29 cells
chemoPv↑, chemopreventive response of AKBA was estimated against intestinal adenomatous polyposis through the inhibition of the Wnt/β-catenin and NF-κB/cyclooxygenase-2 signaling pathway
Wnt↓,
β-catenin/ZEB1↓,
ascitic↓, AKBA by the suppression of ascites,
Let-7↑, AKBA could up-regulate the expression of let-7 and miR-200
miR-200b↑,
eff↑, anti-tumorigenic effects of curcumin and AKBA on the regulation of specific cancer-related miRNAs in colorectal cancer cells, and confirmed their protective action
MMP1↓, . It can inhibit the expression of MMP-1, MMP-2, and MMP-9 mRNAs along with secretions of TNF-α and IL-1β in THP-1 cells.
MMP2↓,
eff↑, combined administration of metformin, an anti-diabetic drug, and boswellic acid nanoparticles exhibited significant synergism through the inhibition of MiaPaCa-2
pancreatic cancer cell proliferation
BioAv↓, BA as a therapeutic drug is its poor bioavailability
BioAv↑, administration of BSE-018 concomitantly with a high-fat meal led to several-fold increased areas under the plasma
concentration-time curves as well as peak concentrations of beta-boswellic acid (betaBA)
Half-Life↓, drug needs to be given orally at the interval of six hours due to its calculated half- life, which was around 6 hrs.
toxicity↓, BSE has been found to be a safe drug without any adverse side reactions, and is well tolerated on oral administration.
Dose↑, Boswellia serrata extract to the maximum amount of 4200 mg/day is not toxic and it is safe to use though it shows poor bioavailability
BioAv↑, Approaches like lecithin delivery form (Phytosome®), nanoparticle delivery systems like liposomes, emulsions, solid lipid nanoparticles, nanostructured lipid carriers, micelles and poly (lactic-co-glycolic acid) nanoparticles
ChemoSen↑, Like any other natural products BA can also be effective as chemosensitizer
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CRC, |
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HCT116 |
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TumCG↓,
TumCCA↑, G1 phase
cycD1/CCND1↓,
cycE/CCNE↓,
CDK2↓,
CDK4↓,
p‑RB1↓,
P21↑,
*antiOx↑, antioxidant (8), anti-inflammatory (9) and anti-obesity (10) properties.
*Inflam↓,
*Obesity↓,
chemoPv↑, Many laboratories have reported that capsaicin possesses chemopreventive and chemotherapeutic effects
Apoptosis↑, Capsaicin has been shown to induce apoptosis in many different types of cancer cell lines including pancreatic (19) colonic (24), prostatic (25), liver (26), esophagieal (27), bladder (28), skin (29), leukemia (30), lung (31), and endothelial cells (
selectivity↑,
TRPV1↑, Transient receptor potential vanilloids (TRPVs) are receptors of capsaicin which lead to Ca2+-mediated mitochondrial damage and cytochrome c release.
Ca+2↑,
mtDam↑,
Cyt‑c↑,
P53↑, Capsaicin was found to induce p53 phosphorylation at the Ser-15 residue (30) and enhanced p53 acetylation through down-regulation of sirtuin 1 (
SIRT1↓,
TumCCA↑, Capsaicin induced G0/G1 phase arrest in human esophageal carcinoma cells with an increase of p21 and a decrease of CDK4, CDK6 and cyclin E (
P21↑,
CDK4↓,
CDK6↓,
cycE/CCNE↓,
angioG↓, Capsaicin has anti-angiogenic properties both in vitro and in vivo
TumMeta↓, Capsaicin treatment significantly reduced the metastatic burden in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice (57).
HO-1↑, capsaicin induced the expression of HO-1 in human hepatoma HepG2 cells through the generation of ROS and subsequent activation of a redox-sensitive transcription factor nuclear factor erythroid related factor-2 (Nrf2)
ROS↑,
NRF2↑,
*lipid-P↓, capsaicin inhibits lipid peroxidation by increasing the activity of a battery of antioxidant enzymes
*SOD↑, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR)
*Catalase↑,
*GPx↑,
*GSR↑,
*PGE2↓, inhibitory effects of capsaicin on the production of prostaglandin E2 (PGE2) in macrophages incubated with LPS or TPA (
*COX2/PTGS2↓, the inhibition of COX-2 and iNOS expression by capsaicin in these cells is mediated in a VR1/TRPV1-independent manner
*iNOS↓,
TumCP↓, anticancer effects of capsaicin are partly mediated through the inhibition of cancer cell proliferation.
TumCCA↑, Capsaicin inhibited the growth of human esophageal epidermoid carcinoma (CE 81T/VGH) cells by arresting the cell cycle at the G1 phase through the downregulation of cyclin E, cyclin dependent kinase (Cdk)-4 and -6,
cycE/CCNE↓,
CDK4↓,
MMP↓, Similarly, the inhibition of Cdk-2,-4 and-6, the generation of ROS, and the loss of mitochondrial membrane potential were associated with reduced proliferation of human bladder cancer cells upon capsaicin treatment
P53↑, capsaicin is mediated through the induction of p53 nd its target gene products such as, p21, and Bax.
P21↑,
BAX↑,
SIRT1↑, The same study also demonstrated that capsaicin induced autophagy in human fetal lung cells by inducing SIRT1
angioG↓, Capsaicin inhibited angiogenesis in the chick chorioallantoic membrane
P-gp/ABCB1↓, Capsaicin inhibited the P-gp activity in human intestinal carcinoma (Caco2) cells in a concentration- and time-dependent manner (
ChemoSen↑, Capsaicin exhibited synergistic growth inhibitory effects with 5-fluorouracil (5FU) in cholangiocarcinoma cells in culture as well as xenograft tumor growth in nude mice
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TumCP↓, We observed that CAPE dosage-dependently suppressed the proliferation of LNCaP, DU-145, and PC-3 human prostate cancer cells.
TumCG↓, Administration of CAPE by gavage significantly inhibited the tumor growth of LNCaP xenografts in nude mice.
TumCCA↑, CAPE caused retardation of xenograft growth and G1 cell cycle arrest in LNCaP cells
AMPK↓, ollowing CAPE treatment, AMPK, SGK1, and NF-κB pathways were down-regulated.
NF-kB↓,
β-catenin/ZEB1↓, This down-regulation likely resulted in the decrease of β-catenin and Creb signaling, cyclin D1 and cyclin E1 expression, Cdk2 and Cdk4 activity, as well as increase of p27Kip1 expression.
CREB↓,
cycD1/CCND1↓,
cycE/CCNE↓,
CDK2↓,
CDK4↓,
TumCP↓, The CHL, at concentrations 25-400 microg/ml, reduced the proliferation of HL-60, K-562, S-180, and MCF-7 cells by 8.2-95.7% after 72 h of incubation.
TumCCA↑, The CHL also accumulated G2/M cells and induced apoptosis in the MCF-7 cells.
Apoptosis↑,
cycD1/CCND1↓, breast carcinoma cells exhibited lower cyclin D1 and cyclin E levels but higher cyclin B1 level after incubation with the CHL
cycE/CCNE↓,
CycB/CCNB1↑,
TumCG↓, inhibition of tumor cell growth via induction of apoptosis, cell-cycle arrest, anti-metastasis and anti-angiogenesis are major promising chemo-preventive actions of cucurbitacins.
Apoptosis↑,
TumCCA↑,
TumMeta↓,
angioG↓,
chemoPv↑,
BioAv↓, CuB has been studied to be ~10% with plasma concentration ranging from 4.85 to 7.81 μg/L after 30 mins of oral dosing.
Half-Life↝, Studies have shown that they reach highest plasma concentration within 1.75 h and an elimination half-life of ~2.5 h.
cycD1/CCND1↓, decreased Cyclin D1 and Cyclin E1 levels.
cycE/CCNE↓,
Casp3↑, CRC cell lines underwent in vitro cell death when exposed to CuB, which was accompanied by caspase-3 and cleaved PARP
cl‑PARP↑,
JNK↑, (TNBC), cucurbitacin E strongly boosted JNK activation while considerably decreasing AKT and ERK activation in MDA-MB-468 cells.
Akt↓,
ERK↓,
survivin↓, also significantly decreased expression of Cyclin D1, Survivin, XIAP, Bcl2 and Mcl-1
XIAP↓,
Bcl-2↓,
Mcl-1↓,
ROS↑, In the pancreatic cancer cell line Capan-1, CuD induced cell-cycle arrest and death via the ROS/p38 pathway [43
NRF2↓, Recent studies have shown that CuIIb and cucurbitacin B induced apoptosis in cervical cancer cell lines by Nrf2 inhibition,
FAK↓, It successfully inhibited angiogenesis by targeting the FAK/MMP-9 signaling axis
MMP9↓,
VEGF↓, suppressed angiogenesis by downregulating the expression of HIF-1 targets, VEGF, VEGFR2 phosphorylation and erythropoietin
VEGFR2/KDR/Flk1↓,
*NF-kB↓, Dietary cucurbitacin E has been shown to reduce inflammation and immunosuppression by downregulating the NF-κB signaling pathway
TLR4↝, Cucurbitacin B was observed to directly bind to toll-like receptor 4 (TLR4) and activate NLRP3 inflammasome, which further ultimately executed pyroptosis in A549 cells.
NLRP3↑,
Pyro↑,
GSH↓, It was observed that treatment with CuI and doxorubicin decreased glutathione (GSH) levels, enhancing cytotoxicity in tumors.
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*toxicity↑, The emergence of natural products has provided extremely valuable references for the treatment of various diseases. Cucurbitacin B, a tetracyclic triterpenoid compound isolated from cucurbitaceae and other plants, is the most abundant member of the c
*antiOx↑, cucurbitacin B and cucurbitacin I have antioxidant properties, which can inhibit lipid peroxides
*Inflam↓, These results suggest that cucurbitacin B can inhibit the activation of NLRP3 inflammasome to inhibit the inflammatory response and cell damage in brain I/R injury.
*NLRP3↓,
*NF-kB↓, cucurbitacins B, E, and I can significantly reduce the activation activity of NF-κB induced by TLR 2/4 agonists in cells.
*neuroP↑, administration of cucurbitacin B has been shown to enhance the generation of new neurons in the hippocampus of ICR and APP/PS1 mice, thereby ameliorating the working memory deficits observed in these mice models
*memory↑,
*GABA↑, Concurrently, cucurbitacin B enhanced the levels of GABA.
*cardioP↑, cucurbitacin B exerts protective effects on the heart, including the prevention of hypertrophy, the amelioration of compromised cardiac function following myocardial infarction,
AntiTum↑, Cucurbitacin B has cytotoxic activity on a variety of tumor cells (Figure 5), and it has a good clinical application prospect as an antitumor drug.
p‑FAK↓, cucurbitacin B inhibited the phosphorylation of FAK and paxillin, and it could also induce the production of reactive oxygen species (ROS), which is helpful for the anti-metastatic potential of the cells.
ROS↑,
TumMeta↑,
TumCP↓, cucurbitacin B induced early apoptosis in these cells and altered the expression of proteins involved in proliferation and apoptosis, such as up-regulating the p53 and p21 genes.
Apoptosis↑,
P53↑,
P21↑,
TumCCA↑, cucurbitacin B affected the cell cycle transition from the G0/G1 phase to the S phase.
p27/CDKN1B↑, cucurbitacin B upregulated the expression of p27 and downregulated the expression of CDK4, CDK2, cyclin D1, and cyclin E mRNA.
CDK4↓,
CDK2↓,
cycD1/CCND1↓,
cycE/CCNE↓,
STAT3↓, inhibiting the STAT3 signaling pathway
ChemoSen↑, combination of cucurbitacin B and cisplatin (DDP) enhanced the activation of caspase-3 and the cleavage of caspase-3 substrate PARP, and it decreased the expression level of pSTAT3.
MMP2↓, It may down-regulate the expression of MMP2, MMP9, and VEGF, which could significantly inhibit cell migration and angiogenesis.
MMP9↓,
VEGF↓,
TumCMig↓,
angioG↓,
NOTCH↓, the Notch signaling pathway in LNCaP cells was down-regulated.
EMT↓, Additionally, it inhibits the epithelial–mesenchymal transition (EMT) mediated by TGF-β1
toxicity↑, Cucurbitacin B exhibits good activity against HepG2 cells, but its high toxicity results in a low therapeutic index (TI).
BioAv↑, Cu-B SLNs can passively target tumors with the EPR effect and show higher accumulation in tumor interstitial space, which can improve the efficacy of cucurbitacin B and reduce the dose.
EPR↑,
PI3K/Akt↓, Deguelin is a well-known PI3K/Akt inhibitor
IKKα↓,
AMP↓,
mTOR↓,
survivin↓,
NF-kB↓,
Apoptosis↑,
TumCCA↑, G1-S phase cell cycle arrest
toxicity↓, No sign of overt toxicity has been observed at the dose of 2–4 mg/kg
HSP90↓,
Casp↑, caspase cascade of apoptosis is initiated
TumCG↓,
p27/CDKN1B↑, found to regulate cell cycle in colon cancer cells by stimulating p27
cycE/CCNE↓,
angioG↓,
Hif1a↓,
VEGF↓,
*toxicity↑, Treatment with deguelin, a potential mitochondria complex I inhibitor (34), reduced tyrosine hydroxylase-positive neurons, leading to Parkinson’s disease (PD).
*BioAv↓, Within the gastrointestinal tract, EA has restricted bioavailability, primarily due to its hydrophobic nature and very low water solubility.
antiOx↓, strong antioxidant properties [12,13], anti-inflammatory effects
Inflam↓,
TumCP↓, numerous studies indicate that EA possesses properties that can inhibit cell proliferation
TumCCA↑, achieved this by causing cell cycle arrest at the G1 phase
cycD1/CCND1↓, reduction of cyclin D1 and E levels, as well as to the upregulation of p53 and p21 proteins
cycE/CCNE↓,
P53↑,
P21↑,
COX2/PTGS2↓, notable reduction in the protein expression of COX-2 and NF-κB as a result of this treatment
NF-kB↓,
Akt↑, suppressing Akt and Notch signaling pathways
NOTCH↓,
CDK2↓,
CDK6↓,
JAK↓, suppression of the JAK/STAT3 pathway
STAT3↓,
EGFR↓, decreased expression of epidermal growth factor receptor (EGFR)
p‑ERK↓, downregulated the expression of phosphorylated ERK1/2, AKT, and STAT3
p‑Akt↓,
p‑STAT3↓,
TGF-β↓, downregulation of the TGF-β/Smad3
SMAD3↓,
CDK6↓, EA demonstrated the capacity to bind to CDK6 and effectively inhibit its activity
Wnt/(β-catenin)↓, ability of EA to inhibit phosphorylation of EGFR
Myc↓, Myc, cyclin D1, and survivin, exhibited decreased levels
survivin↓,
CDK8↓, diminished CDK8 level
PKCδ↓, EA has demonstrated a notable downregulatory impact on the expression of classical isoenzymes of the PKC family (PKCα, PKCβ, and PKCγ).
tumCV↓, EA decreased cell viability
RadioS↑, further intensified when EA was combined with gamma irradiation.
eff↑, EA additionally potentiated the impact of quercetin in promoting the phosphorylation of p53 at Ser 15 and increasing p21 protein levels in the human leukemia cell line (MOLT-4)
MDM2↓, finding points to the ability of reduced MDM2 levels
XIAP↓, downregulation of X-linked inhibitor of apoptosis protein (XIAP).
p‑RB1↓, EA exerted a decrease in phosphorylation of pRB
PTEN↑, EA enhances the protein phosphatase activity of PTEN in melanoma cells (B16F10)
p‑FAK↓, reduced phosphorylation of focal adhesion kinase (FAK)
Bax:Bcl2↑, EA significantly increases the Bax/Bcl-2 rati
Bcl-xL↓, downregulates Bcl-xL and Mcl-1
Mcl-1↓,
PUMA↑, EA also increases the expression of Bcl-2 inhibitory proapoptotic proteins PUMA and Noxa in prostate cancer cells
NOXA↑,
MMP↓, addition to the reduction in MMP, the release of cytochrome c into the cytosol occurs in pancreatic cancer cells
Cyt‑c↑,
ROS↑, induction of ROS production
Ca+2↝, changes in intracellular calcium concentration, leading to increased levels of EndoG, Smac/DIABLO, AIF, cytochrome c, and APAF1 in the cytosol
Endoglin↑,
Diablo↑,
AIF↑,
iNOS↓, decreased expression of Bcl-2, NF-кB, and iNOS were observed after exposure to EA at concentrations of 15 and 30 µg/mL
Casp9↑, increase in caspase 9 activity in EA-treated pancreatic cancer cells PANC-1
Casp3↑, EA-induced caspase 3 activation and PARP cleavage in a dose-dependent manner (10–100 µmol/L)
cl‑PARP↑,
RadioS↑, EA sensitizes and reduces the resistance of breast cancer MCF-7 cells to apoptosis induced by γ-radiation
Hif1a↓, EA reduced the expression of HIF-1α
HO-1↓, EA significantly reduced the levels of two isoforms of this enzyme, HO-1, and HO-2, and increased the levels of sEH (Soluble epoxide hydrolase) in LnCap
HO-2↓,
SIRT1↓, EA-induced apoptosis was associated with reduced expression of HuR and Sirt1
selectivity↑, A significant advantage of EA as a potential chemopreventive, anti-tumor, or adjuvant therapeutic agent in cancer treatment is its relative selectivity
Dose∅, EA significantly reduced the viability of cancer cells at a concentration of 10 µmol/L, while in healthy cells, this effect was observed only at a concentration of 200 µmol/L
NHE1↓, EA had the capacity to regulate cytosolic pH by downregulating the expression of the Na+/H+ exchanger (NHE1)
Glycolysis↓, led to intracellular acidification with subsequent impairment of glycolysis
GlucoseCon↓, associated with a decrease in the cellular uptake of glucose
lactateProd↓, notable reduction in lactate levels in supernatant
PDK1?, inhibit pyruvate dehydrogenase kinase (PDK) -bind and inhibit PDK3
PDK1?,
ECAR↝, EA has been shown to influence extracellular acidosis
COX1↓, downregulation of cancer-related genes, including COX1, COX2, snail, twist1, and c-Myc.
Snail↓,
Twist↓,
cMyc↓,
Telomerase↓, EA, might dose-dependently inhibit telomerase activity
angioG↓, EA may inhibit angiogenesis
MMP2↓, EA demonstrated a notable reduction in the secretion of matrix metalloproteinase (MMP)-2 and MMP-9.
MMP9↓,
VEGF↓, At lower concentrations (10 and 20 μM), EA led to a substantial increase in VEGF levels. However, at higher doses (40 and 100 μM), a notable reduction in VEGF
Dose↝, At lower concentrations (10 and 20 μM), EA led to a substantial increase in VEGF levels. However, at higher doses (40 and 100 μM), a notable reduction in VEGF
PD-L1↓, EA downregulated the expression of the immune checkpoint PD-L1 in tumor cells
eff↑, EA might potentially enhance the efficacy of anti-PD-L1 treatment
SIRT6↑, EA exhibited statistically significant upregulation of sirtuin 6 at the protein level in Caco2 cells
DNAdam↓, increase in DNA damage
Telomerase↓, EGCG stimulates telomere fragmentation through inhibiting telomerase activity.
DNMTs↓, EGCG reduced DNMTs,
cycD1/CCND1↓, EGCG also reduced the protein expression of cyclin D1, cyclin E, CDK2, CDK4, and CDK6. EGCG also inhibited the activity of CDK2 and CDK4, and caused Rb hypophosphorylation
cycE/CCNE↓,
CDK2↓,
CDK4↓,
CDK6↓,
HATs↓, EGCG can inhibit certain biomedically important molecular targets such as DNMTs, HATs, and HDACs
HDAC↓,
selectivity↑, EGCG has shown higher cytotoxicity in cancer cells than in their normal counterparts.
uPA↓, EGCG blocks urokinase, an enzyme which is essential for cancer growth and metastasis
NF-kB↓, EGCG inhibits NFκB and expression of TNF-α, reduces cancer promotion
TNF-α↓,
*ROS↓, It acts as strong ROS scavenger and antioxidant,
*antiOx↑,
Hif1a↓, ↓ HIF-1α; ↓ VEGF; ↓ VEGFR1;
VEGF↓,
MMP2↓, ↓ MMP-2; ↓ MMP-9; ↓ FAK;
MMP9↓,
FAK↓,
TIMP2↑, TIMP-2; ↑
Mcl-1↓, ↓ Mcl-1; ↓ survivin; ↓ XIAP
survivin↓,
XIAP↓,
PCNA↓, ↓ PCNA; ↑ 16; ↑ p18; ↑ p21; ↑ p27; ↑ pRb; ↑ p53; ↑ mdm2
p16↑,
P21↑,
p27/CDKN1B↑,
pRB↑,
P53↑,
MDM2↑,
ROS↑, ↑ ROS; ↑ caspase-3; ↑ caspase-8; ↑ caspase-9; ↑ cytochrome c; ↑ Smac/DIABLO; ↓↑ Bax; Z Bak; ↓ cleaved PPAR;
Casp3↑,
Casp8↑,
Casp9↑,
Cyt‑c↑,
Diablo↑,
BAX⇅,
cl‑PPARα↓,
PDGF↓, ↓ PDGF; ↓ PDGFRb; ↓ EGFR;
EGFR↓,
FOXO↑, activated FOXO transcription factors
AP-1↓, The inhibition of AP-1 activity by EGCG was associated with inhibition of JNK activation but not ERK activation.
JNK↓,
COX2/PTGS2↓, EGCG reduces the activity of COX-2 following interleukin-1A stimulation of human chondrocytes
angioG↓, EGCG inhibits angiogenesis by enhancing FOXO transcriptional activity
TumCCA↑, S-phase arrest
eff↓, The free radical scavenger N-acetylcysteine (NAC) and caspase inhibitors markedly blocked aloe-emodin-induced apoptosis
P53↑,
P21↑,
p27/CDKN1B↑,
cycA1/CCNA1↓,
cycE/CCNE↓,
TS↓,
CDC25↓, Cdc25A
AIF↑, promoted the release of apoptosis-inducing factor (AIF)
proCasp9↓,
Cyt‑c↑,
MMP↓,
Bax:Bcl2↑,
Casp3↑,
Casp9↑,
ROS↑, FA showed promising anticancer activity through underlying mechanisms, including induction of oxidative stress, cytotoxic effect, cell cycle arrest, apoptotic effect, suppression of invasion and migration, antiproliferative effect, autophagy, and gen
TumCCA↑,
TumCI↓,
TumCMig↓,
TumCP↓,
BioAv↑, FA, indicating lower oral bioavailability is affected by the liver's fast conjugation process; this limitation is overcome by applying a nanoformulation of FA.
BioAv↑, medication's bioavailability is 100% when administered intravenously (IV)
TP53↑, FA could impede cell growth by upregulating the gene expression of TP53 and downregulating the gene expression of CDK2, CDK4, and CDK6 in prostate cancer PC-3 cells, resulting in cell cycle arrest in PC-3 cells
CDK2↓,
CDK4↓,
CDK6↓,
JAK2↓, blocking the JAK2/STAT6 immune signaling pathway
STAT6↓,
tyrosinase↓, FA could also decrease tyrosinase activity by directly binding to enzymes
p‑Akt↓, FA lowered phosphorylation of AKT and PI3K in CaSki cells in a dose-dependent way,
p‑PI3K↓,
mTOR↓, FA reduced the amount of mTOR mRNA and Ki-67 protein in A549 lung
Ki-67↓,
Casp3↑, increased the levels of caspase-3 protein
proCasp8↑, FA elevated pro-caspase-3, pro-caspase-8, and pro-caspase-9 and PARP cleavage, Bax, and ROS and decreased Bcl-2, Mcl-1, AKT, and PI3K pathway levels in a dose-dependent way
cl‑PARP↑,
BAX↑,
Bcl-2↓,
Mcl-1↓,
MMP9↓, reducing cell invasion, MMP9 mRNA expression, and cyclin D1 and cyclin E levels
cycD1/CCND1↓,
cycE/CCNE↓,
PINK1↑, FA (100 μg/mL) enhanced apoptosis via increasing PINK-1, Parkin and reducing the MMP expression
PARK2↑,
MMP↓,
CycD3↓, reducing the gene expressions of CCND1, CCND2, CCND3, CDK2, CDK4, and CDK6 level in PC-3 cells
TumAuto⇅, FA has shown anticancer activity via the increase and decrease of autophagy in different types of cancer.
eff↑, by combining with other compounds like 2-deoxy-D-glucose (2DG) [164], epirubicin, gamma radiation [165], aspirin, thyoquinine [166], phenolic and flavonoids, P-coumaric acid [167], 4-vinylguaiacol, caffeic [168], coumaric, and gemcitabine [169].
eff↑, FA and aspirin could trigger apoptotic cell death, p-RB, p21, and p-ERK1/2, cytotoxicity and reduce PCNA and MKI67, growth of tumor in pancreatic cancer.
ALAT↓, figure 5
AST↓,
ALP↓,
VEGF↓,
MMPs↓,
angioG↓,
| - |
in-vitro, |
Cerv, |
HeLa |
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- |
in-vitro, |
Cerv, |
CaSki |
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MMP9↓, FA inhibited cell invasion through reducing MMP-9 mRNA expression.
TumCCA↑, FA induced arrest in G0/G1 phase of the cell cycle in Hela and Caski cells with dose dependent (P < 0.05).
P53↑, FA induced the cell cycle-related proteins expression such as p53 and p21, and reduced Cyclin D1 and Cyclin E levels.
P21↑,
cycD1/CCND1↓,
cycE/CCNE↓,
LC3II↓, FA decreased the autophagy-related proteins such as LC3-II, Beclin1 and Atg12-Atg5 in a dose-dependent manner.
Beclin-1↓,
ATG5↓,
TumCP↓, FA can significantly inhibit cell proliferation and invasion in Hela and Caski cells
TumCI↓, FA inhibited cell invasion
MMP9↓, FA inhibited the cell invasion in Hela and Caski cervical cancer cells through reducing the expression of MMP-9
| - |
in-vitro, |
Colon, |
SW480 |
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- |
in-vitro, |
Colon, |
Caco-2 |
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in-vitro, |
Colon, |
HCT116 |
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TumCP↓, ferulic acid significantly inhibits the proliferation and migration of these cells
TumCMig↓,
TumCCA↑, ferulic acid significantly inhibits the proliferation and migration of these cells
Apoptosis↑,
ATM↑, ferulic acid activates the ATM/Chk2 and ATR/Chk1 pathways
Chk2↑,
ATR↑,
CHK1↑,
CK2↓, down regulating their relative cell cycle regulatory proteins (CDK2 and Cyclin A2 complex, CDK4/6 and Cyclin D1/E1 complex)
cycA1/CCNA1↑, Cyclin A2 complex
CDK4↓,
CDK6↓,
cycD1/CCND1↓,
cycE/CCNE↓,
P53↑,
P21↑,
eff↑, The combination of FZ and DADA exhibited a synergistic effect on inhibiting the proliferation of A549 lung cancer cells.
mt-ROS↑, After 48 h of treatment, the FZ-DADA combination produced reactive oxygen species (ROS) and promoted apoptosis by down-regulating Bcl2 and up-regulating BAX protein expression.
Apoptosis↑, The combination modulates key apoptotic proteins, induces cell cycle arrest, and increases mitochondrial ROS production
Bcl-2↓,
BAX↑,
Casp3↑, The combination activated caspase-3, caspase-7, and PARP, further driving apoptosis in A549 cells
Casp7↑,
PARP↑,
TumCCA↑, The FZ-DADA treatment also induced cell cycle arrest, as evidenced by the inhibition of Cyclin A and Cyclin E proteins.
cycA1/CCNA1↓,
cycE/CCNE↓,
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/CCND1↓, decreasing
the level of the cyclin D1 and cyclin E mRNA
cycE/CCNE↓,
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
Risk↓, Flavonoids, including fisetin, have been linked to a reduced risk of colorectal cancer (CRC)
P53↑, increased levels of p53 and decreased levels of murine double minute 2, contributing to apoptosis induction
MDM2↓,
COX2/PTGS2↓, fisetin inhibits the cyclooxygenase-2 and wingless-related integration site (Wnt)/epidermal growth factor receptor/nuclear factor kappa B signaling pathways
Wnt↓,
NF-kB↓,
CDK2↓, regulating the activities of cyclin-dependent kinase 2 and cyclin-dependent kinase 4, reducing retinoblastoma protein phosphorylation, decreasing cyclin E levels, and increasing p21 levels
CDK4↓,
p‑RB1↓,
cycE/CCNE↓,
P21↑,
NRF2↓, Pandey and Trigun revealed that fisetin induces apoptosis in CRC cells by inhibiting autophagy and suppressing Nrf2
ROS↑, Furthermore, fisetin elevated ROS levels and downregulated Nrf2 expression, indicating Nrf2 suppression in fisetin-induced apoptosis in CRC cells.
Casp8↑, fisetin treatment resulted in the upregulation of various molecular pathways, including cleaved caspase-8, Fas ligand, TRAIL, and DR5 levels, in the cancer cells
Fas↑,
TRAIL↑,
DR5↑,
MMP↓, Fisetin also caused mitochondrial membrane depolarization, leading to the release of Smac/DIABLO and cytochrome c
Cyt‑c↑,
selectivity↑, enhanced cellular uptake, and induction of apoptosis in cancer cells
P450↝, Fisetin also affected the activities of cytochrome P450 (CYP450 3A4) and glutathione-S-transferase
GSTs↝,
RadioS↑, fisetin pretreatment heightened the radiosensitivity of p53-mutant HT29 human CRC cells
Inflam↓, Fisetin suppresses inflammation in the colon and CRC
β-catenin/ZEB1↓, fisetin in treating colon cancer, revealing its capability to effectively downregulate β-catenin and COX-2
EGFR↓, fisetin decreased EGFR and NF-κB activation in HT29 cells
TumCCA↑, It induces cell cycle arrest, disrupting the transition from the G1 to the S phase, as well as causing G2/M phase arrest
ChemoSen↑, intervention with fisetin and 5-FU appeared to extend the lifespan of the experimental animals
*Inflam↓, present in fruits and vegetables such as strawberries, apple, cucumber, persimmon, grape and onion, was shown to possess anti-microbial, anti-inflammatory, anti-oxidant
*antiOx↓, fisetin possesses stronger oxidant inhibitory activity than well-known potent antioxidants like morin and myricetin.
*ERK↑, inducing extracellular signal-regulated kinase1/2 (ERK)/c-myc phosphorylation, nuclear NF-E2-related factor-2 (Nrf2), glutamate cystine ligase and glutathione (GSH) levels
*p‑cMyc↑,
*NRF2↑,
*GSH↑,
*HO-1↑, activate Nrf2 mediated induction of hemeoxygenase-1 (HO-1) important for cell survival
mTOR↓, in our studies on fisetin in non-small lung cancer cells, we found that fisetin acts as a dual inhibitor PI3K/Akt and mTOR pathways
PI3K↓,
Akt↓,
TumCCA↑, fisetin treatment to LNCaP cells resulted in G1-phase arrest accompanied with decrease in cyclins D1, D2 and E and their activating partner CDKs 2, 4 and 6 with induction ofWAF1/p21 and KIP1/p27
cycD1/CCND1↓,
cycE/CCNE↓,
CDK2↓,
CDK4↓,
CDK6↓,
P21↑,
p27/CDKN1B↑,
JNK↑, fisetin could inhibit the metastatic ability of PC-3 cells by suppressing of PI3 K/Akt and JNK signaling pathways with subsequent repression of matrix metalloproteinase-2 (MMP-2) and MMP-9
MMP2↓,
MMP9↓,
uPA↓, fisetin suppressed protein and mRNA levels of MMP-2 and urokinase-type plasminogen activator (uPA) in an ERK-dependent fashion.
NF-kB↓, decrease in the nuclear levels of NF-B, c-Fos, and c-Jun was noted in fisetin treated cells
cFos↓,
cJun↓,
E-cadherin↑, upregulation of E-cadherin and down-regulation of vimentin and N-cadherin.
Vim↓,
N-cadherin↓,
EMT↓, EMT inhibiting potential of fisetin has been reported in melanoma cells
MMP↓, The shift in mitochondrial membrane potential was accompanied by release of cytochrome c and Smac/DIABLO resulting in activation of the caspase cascade and cleavage of PARP
Cyt‑c↑,
Diablo↑,
Casp↑,
cl‑PARP↑,
P53↑, fisetin with induction of p53 protein
COX2/PTGS2↓, Fisetin down-regulated COX-2 and reduced the secretion of prostaglandin E2 without affecting COX-1 protein expression.
PGE2↓,
HSP70/HSPA5↓, It was shown that the induction of HSF1 target proteins, such as HSP70, HSP27 and BAG3 were inhibited in HCT-116 cells exposed to heat shock at 43 C for 1 h in the presence of fisetin
HSP27↓,
DNAdam↑, DNA fragmentation, an increase in the number of sub-G1 phase cells, mitochondrial membrane depolarization and activation of caspase-9 and caspase-3.
Casp3↑,
Casp9↑,
ROS↑, This was associated with production of intracellular ROS
AMPK↑, Fisetin induced AMPK signaling
NO↑, fisetin induced cytotoxicity and showed that fisetin induced apoptosis of leukemia cells through generation of NO and elevated Ca2+ activating the caspase
Ca+2↑,
mTORC1↓, Fisetin was shown to inhibit the mTORC1 pathway and its downstream components including p70S6 K, eIF4B and eEF2 K.
p70S6↓,
ROS↓, Others have also noted a similar decrease in ROS with fisetin treatment.
ER Stress↑, Induction of ER stress upon fisetin treatment, evident as early as 6 h, and associated with up-regulation of IRE1, XBP1s, ATF4 and GRP78, was followed by autophagy which was not sustained
IRE1↑,
ATF4↑,
GRP78/BiP↑,
eff↑, Combination of fisetin and the BRAF inhibitor sorafenib was found to be extremely effective in inhibiting the growth of BRAF-mutated human melanoma cells
eff↑, synergistic effect of fisetin and sorafenib was observed in human cervical cancer HeLa cells,
eff↑, Similarly, fisetin in combination with hesperetin induced apoptosis
RadioS↑, pretreatment with fisetin enhanced the radio-sensitivity of p53 mutant HT-29 cancer cells,
ChemoSen↑, potential of fisetin in enhancing cisplatin-induced cytotoxicity in various cancer models
Half-Life↝, intraperitoneal (ip) dose of 223 mg/kg body weight the maximum plasma concentration (2.53 ug/ml) of fisetin was reached at 15 min which started to decline with a first rapid alpha half-life of 0.09 h and a longer
half-life of 3.12 h.
DNAdam↑, Fisetin induced DNA fragmentation, ROS generation, and apoptosis in NCI-H460 cells via a reduction in Bcl-2 and increase in Bax expression
ROS↑,
Apoptosis↑,
Bcl-2↓,
BAX↑,
cl‑Casp9↑, Fisetin treatment increased cleavage of caspase-9 and caspase-3 thereby increasing caspase-3 activation
cl‑Casp3↑,
Cyt‑c↑, leading to cytochrome-c release
lipid-P↓, Fisetin (25 mg/kg body weight) decreased histological lesions and levels of lipid peroxidation and modulated the enzymatic and nonenzymatic anti-oxidants in B(a)P-treated Swiss Albino mice
TumCG↓, We observed that fisetin treatment (5–20 μM) inhibits cell growth and colony formation in A549 NSC lung cancer cells.
TumCA↓, Another study showed that fisetin inhibits adhesion, migration, and invasion in A549 lung cancer cells by downregulating uPA, ERK1/2, and MMP-2
TumCMig↓,
TumCI↓,
uPA↓,
ERK↓,
MMP9↓,
NF-kB↓, Treatment with fisetin also decreased the nuclear levels of NF-kB, c-Fos, c-Jun, and AP-1 and inhibited NF-kB binding.
cFos↓,
cJun↓,
AP-1↓,
TumCCA↑, Our laboratory has previously shown that treatment of LNCaP cells with fisetin caused inhibition of PCa by G1-phase cell cycle arrest
AR↓, inhibited androgen signaling and tumor growth in athymic nude mice
mTORC1↓, induced autophagic cell death in PCa cells through suppression of mTORC1 and mTORC2
mTORC2↓,
TSC2↑, activated the mTOR repressor TSC2, commonly associated with inhibition of Akt and activation of AMPK
EGF↓, Fisetin also inhibits EGF and TGF-β induced YB-1 phosphorylation and EMT in PCa cells
TGF-β↓,
EMT↓, Fisetin also inhibits EGF and TGF-β induced YB-1 phosphorylation and EMT in PCa cells
P-gp/ABCB1↓, decrease the P-gp protein in multidrug resistant NCI/ADR-RES cells.
PI3K↓, Fisetin also inhibited the PI3K/AKT/NFkB signaling
Akt↓,
mTOR↓, Fisetin inhibited melanoma progression in a 3D melanoma skin model with downregulation of mTOR, Akt, and upregulation of TSC
eff↑, combinational treatment study of melatonin and fisetin demonstrated enhanced antitumor activity of fisetin
ROS↓, Fisetin inhibited ROS and augmented NO generation in A375 melanoma cells
ER Stress↑, induction of ER stress evidenced by increased IRE1α, XBP1s, ATF4, and GRP78 levels in A375 and 451Lu cells.
IRE1↑,
ATF4↑,
GRP78/BiP↑,
ChemoSen↑, combination of fisetin with sorafenib effectively inhibited EMT and augmented the anti-metastatic potential of sorafenib by reducing MMP-2 and MMP-9 proteins in melanoma cell xenografts
CDK2↓, Fisetin (0–60 μM) was shown to inhibit activity of CDKs dose-dependently leading to cell cycle arrest in HT-29 human colon cancer cells
CDK4↓, Fisetin treatment decreased activities of CDK2 and CDK4 via decreased levels of cyclin-E, cyclin-D1 and increase in p21 (CIP1/WAF1) levels.
cycE/CCNE↓,
cycD1/CCND1↓,
P21↑,
COX2/PTGS2↓, fisetin (30–120 μM) induces apoptosis in colon cancer cells by inhibiting COX-2 and Wnt/EGFR/NF-kB -signaling pathways
Wnt↓,
EGFR↓,
β-catenin/ZEB1↓, Fisetin treatment inhibited Wnt/EGFR/NF-kB signaling via downregulation of β-catenin, TCF-4, cyclin D1, and MMP-7
TCF-4↓,
MMP7↓,
RadioS↑, fisetin treatment was found to radiosensitize human colorectal cancer cells which are resistant to radiotherapy
eff↑, Combined treatment of fisetin with NAC increased cleaved caspase-3, PARP, reduced mitochondrial membrane potential with induction of caspase-9 in COLO25 cells
NRF2↑, fisetin increased the protein level and accumulation Nrf2 and down regulated the protein levels of Keap1
Keap1↓,
ChemoSen↑, In vitro studies showed that fisetin and quercetin could also act against chemotherapeutic resistance in several cancers
BioAv↓, Fisetin has low aqueous solubility and bioavailability
Cyt‑c↑, release of cytochrome c from mitochondria, caspase-3 and caspase-9 mRNA and protein expression, and B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated X (Bax) levels, were found to be regulated in the fisetin-treated cancer cell line
Casp3↑,
Casp9↑,
BAX↑,
tumCV↓, fisetin at 5–80 µM significantly reduced the viability of A431 human epidermoid carcinoma cells by the release of cytochrome c,
Mcl-1↓, reducing the anti-apoptotic protein expression of Bcl-2, Bcl-xL, and Mcl-1 along with elevation of pro-apoptotic protein expression (Bax, Bak, and Bad) and caspase cleavage and poly-ADP-ribose polymerase (PARP) protein
cl‑PARP↑,
IGF-1↓, fisetin promoted caspase-8 and cytochrome c expression, possibly by impeding the aberrant activation of insulin growth factor receptor 1 and Akt
Akt↓,
CDK6↓, fisetin binds with CDK6, which in turn blocks its activity with an inhibitory concentration (IC50) at a concentration of 0.85 μM
TumCCA↑, fisetin is identified as a regulator of cell cycle checkpoints, leading to cell arrest through CDK inhibition in HL60 cells and astrocyte cells over the G0/G1, S, and G2/M phases
P53?, exhibiting elevated levels of p53
cycD1/CCND1↓, 10–60 μM fisetin concentration, prostate cancer cells PC3, LNCaP, and CWR22Ry1 had decreased cellular viability and decreased levels of D1, D2, and E cyclins and their activating partners CDK2, and CDKs 4/ 6,
cycE/CCNE↓,
CDK2↓, decreased levels of D1, D2, and E cyclins and their activating partners CDK2, and CDKs 4/ 6,
CDK4↓,
CDK6↓,
MMP2↓, fisetin displayed tumor inhibitory effects by blocking MMP-2 and MMP-9 at mRNA and protein levels in prostate PC-3 cells
MMP9↓,
MMP1↓, Similarly, fisetin can also inhibit MMP-1, MMP-9, MMP-7, MMP-3, and MMP-14 gene expression linked with ECM remodeling in human umbilical vascular endothelial cells (HUVECs) and HT-1080 fibrosarcoma cells [9
MMP7↓,
MMP3↓,
VEGF↓, fisetin in a concentration-dependent manner (10–50 μM concentration) significantly inhibited regular serum, growth-enhancing supplement, and vascular endothelial growth factor (VEGF)
PI3K↓, fisetin inhibited PI3K expression and phosphorylation of Akt
mTOR↓, fisetin treatment activated the apoptotic process through inhibiting both PI3K and mammalian target of rapamycin (mTOR) signaling pathways
COX2/PTGS2↓, fisetin resulted in activation of apoptosis and inhibition of COX-2 and the Wnt/EGFR/NF-kB pathway
Wnt↓,
EGFR↓,
NF-kB↓,
ERK↓, Fisetin is one of the flavonoids that has been found to suppress ERK1/2 signaling in human gastric (SGC7901), hepatic (HepG2), colorectal (Caco-2)
ROS↑, fisetin induced ROS generation and suppressed ERK through its phosphorylation
angioG↓, fisetin-induced anti-angiogenesis led to reduced VEGF and epidermal growth factor receptor (EGFR) expression
TNF-α↓, Fisetin suppressed IL-1β-mediated expression of inducible nitric oxide synthase, nitric oxide, interleukin-6, tumor necrotic factor-α, prostaglandin E2, cyclooxygenase-2 (iNOS, NO, IL-6, TNF-α, PGE2, and COX-2),
PGE2↓,
iNOS↓,
NO↓,
IL6↓,
HSP70/HSPA5↝, fisetin-mediated inhibition of cellular proliferation by HSP70 and HSP27 regulation
HSP27↝,
MMP↓, fraction of cells with reduced mitochondrial membrane potential also increased, indicating that fisetin-induced apoptosis also destroys mitochondria.
mtDam↑,
Cyt‑c↑, Cytochrome c and Smac/DIABLO levels are also released when the mitochondrial membrane potential changes, and this results in the activation of the caspase cascade and the cleavage of poly [ADP-ribose] polymerase (PARP)
Diablo↑,
Casp↑,
cl‑PARP↑,
Bak↑, Fisetin induced apoptosis in HCT-116 human colon cancer cells by upregulating proapoptotic proteins Bak and BIM and downregulating antiapoptotic proteins B cell lymphoma (BCL)-XL and -2.
BIM↑,
Bcl-xL↓,
Bcl-2↓,
P53↑, fisetin through the activation of p53
ROS↑, over generation of ROS, which is also directly initiated by fisetin, the stimulation of AMPK
AMPK↑,
Casp9↑, activating caspase-9 collectively, then activating caspase-3, leading to apopotosis
Casp3↑,
BID↑, Bid, AIF and the increase of the ratio of Bax to Bcl-2, causing the activation of caspase 3–9
AIF↑,
Akt↓, The inhibition of the Akt/mTOR/MAPK/
mTOR↓,
MAPK↓,
Wnt↓, Fisetin has been shown to degrade the Wnt/β/β-catenin signal
β-catenin/ZEB1↓,
TumCCA↑, fisetin triggered G1 phase arrest in LNCaP cells by activating WAF1/p21 and kip1/p27, followed by a reduction in cyclin D1, D2, and E as well as CDKs 2, 4, and 6
P21↑,
p27/CDKN1B↑,
cycD1/CCND1↓,
cycE/CCNE↓,
CDK2↓,
CDK4↓,
CDK6↓,
TumMeta↓, reduces PC-3 cells' capacity for metastasis
uPA↓, fisetin decreased MMP-2 protein, messenger RNA (mRNA), and uPA levels through an ERK-dependent route
E-cadherin↑, Fisetin can upregulate the epithelial marker E-cadherin, downregulate the mesenchymal marker vimentin, and drastically lower the EMT regulator twist protein level at noncytotoxic dosages, studies have revealed.
Vim↓,
EMT↓,
Twist↓,
DNAdam↑, Fisetin induces apoptosis in the human nonsmall lung cancer cell line NCI-H460, which causes DNA breakage, the growth of sub-G1 cells, depolarization of the mitochondrial membrane, and activation of caspases 9, 3, which are involved in prod of iROS
ROS↓, fisetin therapy has been linked to a reduction in ROS, according to other research.
COX2/PTGS2↓, Fisetin lowered the expression of COX-1 protein, downregulated COX-2, and decreased PGE2 production
PGE2↓,
HSF1↓, Fisetin is a strong HSF1 inhibitor that blocks HSF1 from binding to the hsp70 gene promoter.
cFos↓, NF-κB, c-Fos, c-Jun, and AP-1 nuclear levels were also lowered by fisetin treatment
cJun↓,
AP-1↓,
Mcl-1↓, inhibition of Bcl-2 and Mcl-1 all contribute to an increase in apoptosis
NF-kB↓, Fisetin's ability to prevent NF-κB activation in LNCaP cells
IRE1↑, fisetin (20–80 µM) was accompanied by brief autophagy and the production of ER stress, which was shown by elevated levels of IRE1 α, XBP1s, ATF4, and GRP78 in A375 and 451Lu cells
ER Stress↑,
ATF4↑,
GRP78/BiP↑,
MMP2↓, lowering MMP-2 and MMP-9 proteins in melanoma cell xenografts
MMP9↓,
TCF-4↓, fisetin therapy reduced levels of β-catenin, TCF-4, cyclin D1, and MMP-7,
MMP7↓,
RadioS↑, fisetin treatment could radiosensitize human colorectal cancer cells that are resistant to radiotherapy.
TOP1↓, fisetin blocks DNA topoisomerases I and II in leukemia cells.
TOP2↓,
*memory↑, Oral administration of fisetin was shown to enhance learning and memory in mice [10]. In addition, it has anti-inflammatory activity and has been shown to inhibit the activity of 5-lipoxygenase in microglia cells,
*Inflam↓,
*5LO↓,
*lipid-P↓, thereby reducing the production of lipid peroxides and their pro-inflammatory by-products
*NF-kB↓, Of the nine different flavones tested, fisetin was the most potent in suppressing tumor necrosis factor (TNF)-induced NF-κB activation.
*antiOx↑, Fisetin not only has direct antioxidant activity but can also increase the intracellular levels of glutathione, the major intracellular antioxidant.
*GSH↑,
*HO-1↑, induction of Heme Oygenase-1 expression via NF-E2-related factor 2 activation may contribute to the cytoprotection exerted by fisetin against oxidative stress
*NRF2↑,
*ROS↓,
PI3K↓, Prostate: ↓ PI3-K (p85) expression [33] ↓ Akt phosphorylation at Ser473 & Thr308
Akt↓,
TumCCA↑, Induces cell cycle arrest in G1 phase ↓ cyclins D1, D2 and E ↓ cdks 2, 4
cycD1/CCND1↓,
cycE/CCNE↓,
CDK2↓,
CDK4↓,
TumCMig↓, ↓ migration, invasion through MMP suppression
MMPs↓,
PSA↓, ↓ serum PSA levels
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Pca, |
LNCaP |
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in-vitro, |
Pca, |
PC3 |
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in-vitro, |
Pca, |
22Rv1 |
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Dose↝, Treatment of fisetin (10–60 μM, 48 h) was found to result in a decrease in the viability of LNCaP, CWR22Rυ1 and PC-3 cells but had only minimal effects on normal prostate epithelial cells
tumCV↓,
selectivity↑,
TumCCA↑, Treatment of LNCaP cells with fisetin also resulted in G1-phase arrest that was associated with a marked decrease in the protein expression of cyclins D1, D2 and E
cycD1/CCND1↓,
cycE/CCNE↓,
CDK2↑, activating partner cyclin-dependent kinases 2, 4 and 6 with concomitant induction of WAF1/p21 and KIP1/p27.
CDK4↑,
CDK6↑,
P21↑,
p27/CDKN1B↑,
Apoptosis↑, Fisetin treatment also resulted in induction of apoptosis, poly (ADP-ribose) polymerase (PARP) cleavage
cl‑PARP↑,
Cyt‑c↑, induction of mitochondrial release of cytochrome c into cytosol, downregulation of X-linked inhibitor of apoptosis protein
XIAP↓,
Casp3↑, significant activation of caspases-3, -8 and -9
Casp8↑,
Casp9↑,
Bcl-2↓, In sharp contrast, the protein expression of Bcl-2 was significantly decreased by fisetin treatment in a dose-dependent fashion
PI3K↓, Inhibition of PI3K and phosphorylation of Akt protein expression by fisetin in LNCaP cells
Akt↓,
TumCG↓, Fisetin dose dependently inhibited both cell growth and DNA synthesis (P < 0.05), with a 79 +/- 1% decrease in cell number observed 72 h after the addition of 60 micromol/L fisetin.
TumCCA↑, Perturbed cell cycle progression from the G(1) to S phase was observed at 8 h with 60 micromol/L fisetin treatment, whereas a G(2)/M phase arrest was observed after 24 h (P < 0.05).
CDK2↓, Fisetin decreased the activities of cyclin-dependent kinases (CDK)2 and CDK4;
CDK4↓,
cycE/CCNE↓, hese effects were likely attributable to decreases in the levels of cyclin E and D1 and an increase in p21(CIP1/WAF1) levels
cycD1/CCND1↓,
P21↑,
tumCV↓, GA reduced the viability of K562 cells in a dose and time dependent manner
TumCCA↑, G0/G1 phase arrest
P21↑,
p27/CDKN1B↑,
cycD1/CCND1↓,
cycE/CCNE↓,
Bax:Bcl2↑,
Cyt‑c↑, leakage of cytochrome c
cl‑PARP↓,
DNAdam↑,
Casp3↑,
FASN↓,
Casp8↑,
AntiCan↑, Natural gallic acid (GA) is noted to have anticancer properties for oncogene expression, cycle arrest, apoptosis, angiogenesis, migration and metastasis in various cancers.
TumCCA↑,
angioG↓,
TumCMig↓,
TumMeta↓,
CSCs↓, In two types of embryonic CSCs, GA effectively induced cell death via late apoptosis
Apoptosis↑,
P21↑, GA showed the G0/G1 cell cycle arrest activity in embryonic CSCs by inducing the increase of p21, p27 and p53 expression and the decrease of CDK4, cyclin E and cyclin D1 expression.
P53↑,
p27/CDKN1B↑,
CDK4↓,
cycE/CCNE↓,
cycD1/CCND1↓,
SOX2↓, GA inhibited the expression levels of mRNA and protein for stem cell markers, such as SOX2, NANOG and OCT4, in NTERA-2 and NCCIT cells.
Nanog↓,
OCT4↓,
ROS↑, The induction of cellular and mitochondrial reactive oxygen species by GA also activated the cellular DNA damage response pathway by raising the phosphorylated-BRCA1, ATM, Chk1, Chk2 and histone.
DNAdam↑,
BRCA1↑,
ATM↑,
CHK1↑,
Chk2↑,
Histones↑,
TumCI↓, GA inhibited CSCs invasion and migration by inhibiting the expression of matrix metalloproteinase by the downregulation of EGFR/JAK2/STAT5 signaling pathway.
MMPs↓,
EGFR↓,
JAK2↓,
STAT5↓,
| - |
in-vitro, |
BC, |
MDA-MB-231 |
|
|
|
- |
in-vitro, |
BC, |
HS587T |
|
|
|
- |
in-vitro, |
Nor, |
MCF10 |
|
|
|
AntiTum↑, Gallic acid (GA) possesses potential antitumoral activity on different types of malignancies.
tumCV↓, We observed that GA treatment significantly decreased the cell viability of human TNBC cell line MDA-MB-231 and HS578T in a dose-dependent manner.
selectivity↑, GA exerted a relative lower cytotoxicity on noncancer breast fibroblast MCF-10F
TumCCA↑, GA led to an increase of G0/G1 and sub-G1 phase ratio in MDA-MB-231 cells
cycD1/CCND1↓, GA downregulated cyclin D1/CDK4 and cyclin E/CDK2, upregulated p21and p27, and induced activation of caspase-9 and caspase-3.
CDK4↓,
cycE/CCNE↓,
CDK2↓,
P21↑,
p27/CDKN1B↑,
Casp9↑,
Casp3↑,
ROS↑, previous studies have shown that GA induces apoptosis in cancer cells in associations with oxidative stresses derived from reactive oxygen species, mitochondrial dysfunction, and an increase in intracellular
Ca2 + level
mtDam↑,
i-Ca+2↑,
*ROS↓, However, GA also exhibits antiapoptotic activity in normal human lymphocytes [16] and acts as strong natural antioxidant scavenging reactive oxygen species
*Apoptosis↓,
TumCG↓, GA reduced cell growth of TNBC cell MDA-MB-231 and Hs578T
AntiCan↑, Hibiscus sabdariffa (HS) plant, including anthocyanin, flavonoids, saponins, tannins, polyphenols, organic acids, caffeic acids, citric acids, protocatechuic acid, and others, extracts of this plant have been reported to have anti-cancer effects.
TumCP↓, These compounds have been shown to reduce cancer cell proliferation, induce apoptosis, and cause cell cycle arrest.
Apoptosis↑,
TumCCA↑,
P53↑, They also increase the expression levels of the cell cycle inhibitors (p53, p21, and p27) and the pro-apoptotic proteins (BAD, Bax, caspase 3, caspase 7, caspase 8, and caspase 9).
P21↑,
p27/CDKN1B↑,
BAD↑,
BAX↑,
Casp3↑,
Casp7↑,
Casp8↑,
Casp9↑,
*AntiBio↑, Anti-microbial effect
*Inflam↓, Anti-inflammatory effect
*antiOx↑, In calyces of HS, compounds such as anthocyanins have antioxidant properties
*BP↓, The tea made from the HS leaves effectively lowers the blood pressure level in patients because of the presence of phytochemicals that induce systemic vasodilation along
*AntiDiabetic↑, calyces extract of HS can reduce the blood sugar level in diabetic patients
HDAC1↓, HS extract mediated inhibitory responses which were attributed to their inhibition of histone deacetylases (HDACs), specifically HDAC1 and HDAC3.
HDAC3↓,
tumCV↓, PCA dependently decreased cell viability, increased lactate dehydrogenase (LDH) leakage, enhanced DNA fragmentation, reduced mitochondrial membrane potential
LDL↓,
DNAdam↑,
MMP↓,
*Catalase↑, Ethanolic extract of the HS substantially increases the levels of the antioxidants CAT, SOD, GPx and reduced glutathione (GSH) in brain tissue, thus possessing significant antioxidant activity.
*SOD↑,
*GPx↑,
*GSH↑,
*antiOx↑,
*ROS↓, Anthocyanin in the extract of HS acts on the anti-oxidant system, and scavenges free radicals thus reducing damage to genomes of regular cells and the mutations, thus stopping tumor formation
TumCMig↓, PCA found in extract of HS inhibited cell migration and invasion to non-cytotoxic cells via down-regulation of the Ras/Akt/NF-κβ pathway and MMP-2 production [92].
TumCI↓,
selectivity↑,
RAS↓,
Akt↓,
NF-kB↓,
MMP2↓,
PI3K↓, decreasing PI3K, P-Akt protein, MMP expression, anti-apoptotic Bcl-2, Bcl-xL proteins, and PCNA, cyclin A, D1, B1, and E.
Bcl-2↓,
Bcl-xL↓,
PCNA↓,
cycA1/CCNA1↓,
cycD1/CCND1↓,
cycE/CCNE↓,
AntiCan↑, honokiol possesses anti-carcinogenic, anti-inflammatory, anti-oxidative, anti-angiogenic as well as inhibitory effect on malignant transformation of papillomas to carcinomas in vitro and in vivo animal models without any appreciable toxicity.
Inflam↓,
antiOx↑,
selectivity↑,
*toxicity↓,
cycD1/CCND1↓, honokiol resulted in inhibition of UVB-induced expression levels of cyclins (cyclins D1, D2, and E) and CDKs in skin tumors
cycE/CCNE↓,
CDK2↓,
CDK4↓,
TumMeta↓, Honokiol Inhibits Metastatic Potential of Melanoma Cells
NADPH↓, Honokiol not only reduces the NADPH oxidase activity
MMP2↓, honokiol treatment reduces the expression of MMP-2 and MMP-9
MMP9↓,
p‑mTOR↓, honokiol caused significant downregulation of mTOR phosphorylation
EGFR↓, honokiol decreases the expression levels of total EGFR
EMT↓, honokiol effectively inhibits EMT in breast cancer cells
SIRT1↑, onokiol increases the expressions of SIRT1 and SIRT3,
SIRT3↑,
EZH2↓, depletion of EZH2 by honokiol treatment inhibited cell proliferation
Snail↓, significantly down regulates Snail, vimentin, N-cadherin expression, and upregulates cytokeratin-18 and E-cadherin expression
Vim↓,
N-cadherin↓,
E-cadherin↑,
COX2/PTGS2↓, honokiol as an inhibitor of COX-2 expression
NF-kB↓, inhibited transcriptional activity of NF-jB,
*ROS↓, Inhibition of UVR-induced inflammatory mediators as well as ROS by honokiol treatment contributes to the prevention of UVR-induced skin tumor development
Ca+2↑, excessive influx of cytosolic calcium ion into the mitochondria triggers dysfunction of the mitochon-
drial membrane permeabilization with mitochondrial ROS induction
ROS↑,
| - |
in-vitro, |
Pca, |
LNCaP |
|
|
|
- |
in-vitro, |
Pca, |
C4-2B |
|
|
|
TumCP↓, Treatment of LNCaP and C4–2 prostate cancer cells with HT resulted in a dose-dependent inhibition of proliferation
selectivity↑, This was in contrast to HT’s ineffectiveness against normal prostate epithelial cells RWPE1 and PWLE2, suggesting cancer cells-specific effect.
TumCCA↑, HT induced G1/S cell cycle arrest, with inhibition of cyclins D1/E and cdk2/4, and induction of inhibitory p21/p27. HT also induced apoptosis
cycD1/CCND1↓,
cycE/CCNE↓,
CDK2↓,
CDK4↓,
P21↑,
p27/CDKN1B↑,
Apoptosis↑, HT also induced apoptosis, as confirmed by flow cytometry, caspase activation, PARP cleavage and BAX/Bcl-2 ratio.
Casp↑,
cl‑PARP↑,
Bax:Bcl2↑, HT inhibits the expression of pro-survival Bcl-2, with concomitant induction of apoptosis-inducing BAX, this tilts the balance in favor of BAX in the cancer cells, marked by increased BAX/Bcl-2 ratio
p‑Akt↓, It inhibited the phosphorylation of Akt / STAT3, and induced cytoplasmic retention of NF-κB,
p‑STAT3↓,
NF-kB↓, transcriptional activity of NF-κB was considerably decreased, dose-dependently, by HT in both the cell lines
AR↓, HT downregulates AR expression
ROS↑, In colon cancer cells, HT has been shown to generate ROS leading to apoptotic cell death and mitochondrial dysfunction. Even in prostate cancer PC3 cells, there is evidence for ROS generation by HT
*BioAv↓, Despite the promising anticancer activity of HT, there have been concerns about its poor bioavailability owing to its extensive metabolism
*toxicity∅, HT is a ‘safe’ compound and can be administered at higher doses without signs of any genotoxic or mutagenic effects
JNK↑, indole-3-carbinol has been shown to activate the stress-induced MAP kinases p38 and c-jun N-terminal kinase (JNK) in prostate cancer cells (66), and to inhibit constitutively active STAT3,
STAT3↓,
TumCCA↑, Indole-3-carbinol and DIM exhibit the ability to cause G1 arrest in breast and prostate cancer cells
P21↑, upregulation of the CDK inhibitors p21WAF1 and p27kip1, and the concurrent downregulation of cyclin D1, cyclin E, and CDKs 2, 4, and 6,
p27/CDKN1B↑,
cycD1/CCND1↓,
cycE/CCNE↓,
CDK2↓,
CDK4↓,
CDK6↓,
AhR↑, indole-3-carbinol has been reported to increase AhR expression in MCF-7 cells
ER-α36↓, Indole-3-carbinol is a negative regulator of ERα signaling in human tumor cells
ChemoSen↑, Consequently, indole-3-carbinol could cooperate with tamoxifen to inhibit breast cancer proliferation
ER Stress↑, indole-3-carbinol and DIM induced endoplasmic reticulum stress responses in cancer cells via unfolded protein response pathways,
UPR↑,
BRCA1↑, indole-3-carbinol/DIM-induced endoplasmic reticulum stress and upregulation of the expression of the tumor suppressor genes BRCA1 and BRCA2 in prostate and breast cancer cells
BRCA2↑,
TumCMig↓, Indole-3-carbinol has been reported to inhibit the migration and invasion of breast cancer cells
TumCI↓,
VEGF↓, decreased vascular endothelial growth factor (VEGF), increased interleukin-8 (IL-8) secretion, and decreased activities of MMP-2 and MMP-9
IL8↓,
MMP2↓,
MMP9↓,
RadioS↑, Chemo- and radiosensitizing effects of indole-3-carbinol/DIM
Akt↓, Inhibition of Akt/NF-κB signaling
NF-kB↓,
DR4↑, Induction of death receptor (DR)4 and DR5 expression
DR5↑,
chemoPv↑, Cancer chemopreventive effects of inositol hexaphosphate (IP6), a dietary constituent, have been demonstrated against a variety of experimental tumors
TumCG↓, A significant dose- as well as time-dependent growth inhibition was observed in IP6-treated cells, which was associated with an increase in G1 arrest.
TumCCA↑,
P21↓, IP6 strongly increased the expression of CDKIs (cyclin-dependent kinase inhibitors), Cip1/p21 and Kip1/p27
p27/CDKN1B↑,
CDK2↓, IP6 inhibited kinase activities associated with CDK2, 4 and 6, and cyclin E and D1.
CDK4↓,
CDK6↓,
cycE/CCNE↓,
cycD1/CCND1↓,
pRB↑, IP6 increased hypophosphorylated levels of Rb-related proteins, pRb/p107 and pRb2/p130,
Apoptosis↑, IP6 caused a marked increase in apoptosis, which was accompanied by increased levels of cleaved PARP and active caspase 3.
cl‑PARP↑,
Casp3↑,
AntiTum↑, ISL has been also shown to have anti-tumor properties in a number of cancer cell backgrounds.
TumCP⇅, Using a range of ISL from 200nM to 200μM, we discovered that ISL promoted cell proliferation at a low concentration, yet potently inhibited proliferation at the highest concentration.
cycD1/CCND1↓, down-regulation of transcript for cyclin D2 and E2 and a strong induction of mRNA and protein for the cyclin dependent kinase inhibitor Cdkn1a (p21).
cycE/CCNE↓,
P21↑,
EZH2↓, Human prostate cancer DU145 and PC-3 cells, which possess high constitutive EZH2 expression, were treated with 5-20 µM luteolin at various times significantly inhibited EZH2
cycD1/CCND1↓, Mechanistic investigations revealed that miR-26a overexpression suppressed cell cycle regulatory molecules such as cyclin D and E, cyclin dependent kinases CDK4 and CDK6
cycE/CCNE↓,
CDK4↓,
CDK6↓,
TumCCA↑, lycopene impedes the progress of the cell cycle from the G1 to the S phase, primarily by diminishing the cyclin D and cyclin E levels.
cycD1/CCND1↓,
cycE/CCNE↓,
CDK2↓, causes a subsequent inactivation of CDK4 and CDK2 through a reduced phosphorylation of Rb
CDK4↓,
P21↑, lycopene elevates CDK inhibitor, p21, and p53 (tumor suppressor) levels
P53↑,
GSK‐3β↓, Finally, GSK3β, p21, p27, Bad, caspase 9, and p53 (via Mdm2) are inactivated
p27/CDKN1B↓,
Akt↓, lycopene inhibits AKT (protein kinase B) and mTOR
mTOR↓,
ROS↓, ability of lycopene to minimize ROS formation and mitigate oxidative stress
MMPs↓, lycopene may decrease the activity of metalloproteinases of the matrix and prevent SK-Hep1 cellular adhesion, invasion, and migration
TumCI↓,
TumCMig↓,
NF-kB↓, well-documented that lycopene inhibits NF-kB binding activity
*iNOS↓, They also claimed that the lycopene caused a decline in the LPS-induced protein and mRNA expression of iNOS,
*COX2/PTGS2↓, Lycopene can therefore decrease the gene expression of iNOS and COX-2 as a non-toxic agent via controlling pro-inflammatory genes
lipid-P↓, suppress gastric cancer by multimodal mechanisms of reduction in lipid peroxidation, elevation in the levels of antioxidants, and enhanced GSH
GSH↑,
NRF2↑, Reportedly, lycopene is known to “upregulate” this ARE system via Nrf2 in vitro (HepG2 and MCF-7 cells)
antiOx↑, lycopene provides a strong antioxidant activity that is 100 times more effective than α-tocopherol and more than double effective that of β-carotene
TumCP↓, In vivo and in vitro experiments have demonstrated that lycopene at near physiological levels (0.5−2 μM) could inhibit cancer cell proliferation [[22], [23], [24]], induce apoptosis [[25], [26], [27]], and suppress metastasis [
Apoptosis↑,
TumMeta↑,
ChemoSen↑, lycopene can increase the effect of anti-cancer drugs (including adriamycin, cisplatin, docetaxel and paclitaxel) on cancer cell growth and reduce tumour size
BioAv↓, low water solubility and bioavailability of lycopene
Dose↝, The concentration of lycopene in plasma (daily intake of 10 mg lycopene) is approximately 0.52−0.6 μM
BioAv↓, significant decrease in lycopene bioavailability in the elderly
BioAv↑, oils and fats favours the bioavailability of lycopene [80], while large molecules such as pectin can hinder the absorption of lycopene in the small intestine due to their action on lipids and bile salt molecules
SOD↑, GC: 50−150 mg/kg BW/day ↑SOD, CAT, GPx ↑IL-2, IL-4, IL-10, TNF-α ↑IgA, IgG, IgM ↓IL-6
Catalase↑,
GPx↑,
IL2↑, lycopene treatment significantly enhanced blood IL-2, IL-4, IL-10, TNF-α levels and reduced IL-6 level in a dose-dependent manner.
IL4↑,
IL1↑,
TNF-α↑,
GSH↑, GC: ↑GSH, GPx, GST, GR
GPx↑,
GSTA1↑,
GSR↑,
PPARγ↑, ↑GPx, SOD, MDA ↑PPARγ, caspase-3 ↓NF-κB, COX-2
Casp3↑,
NF-kB↓,
COX2/PTGS2↓,
Bcl-2↑, AGS cells Lycopene 5 μM ↑Bcl-2 ↓Bax, Bax/Bcl-2, p53 ↓Chk1, Chk2, γ-H2AX, DNA damage ↓ROS Phase arrest
BAX↓,
P53↓,
CHK1↓,
Chk2↓,
γH2AX↓,
DNAdam↓,
ROS↓,
P21↑, CRC: ↑p21 ↓PCNA, β-catenin ↓COX-2, PGE2, ERK1/2 phosphorylated
PCNA↓,
β-catenin/ZEB1↓,
PGE2↓,
ERK↓,
cMyc↓, AGS cells: ↓Wnt-1, c-Myc, cyclin E ↓Jak1/Stat3, Wnt/β-catenin alteration ↓ROS
cycE/CCNE↓,
JAK1↓,
STAT3↓,
SIRT1↑, Huh7: ↑SIRT1 ↓Cells growth ↑PARP cleavage ↓Cyclin D1, TNFα, IL-6, NF-κB, p65, STAT3, Akt activation ↓Tumour multiplicity, volume
cl‑PARP↑,
cycD1/CCND1↓,
TNF-α↓,
IL6↓,
p65↓,
MMP2↓, SK-Hep1 human hepatoma cells Lycopene 5, 10 μM ↓MMP-2, MMP-9 ↓
MMP9↓,
Wnt↓, AGS cells Lycopene 0.5 μM, 1 μM ↓Wnt-1, c-Myc, cyclin E ↓Jak1/Stat3, Wnt/β-catenin alteration ↓ROS
*antiOx↑, Lycopene, the main pigment of tomatoes, possess the strongest antioxidant activity among carotenoids. Lycopene has unique structure and chemical properties.
TumCP↓, the anticancer of lycopene is also considered to be an important determinant of tumor development including the inhibition of cell proliferation, inhibition of cell cycle progression, induction of apoptosis, inhibition of cell invasion, angiogenesis
TumCCA↓,
Apoptosis↑,
TumCI↓,
angioG↓,
TumMeta↓,
*Risk↓, and may be associated with a decreased risk of different types of cancer.
cycD1/CCND1↓, Several studies suggested lycopene decreased cell cycle related proteins, such as cyclin D1, D3 and E, the cyclin-dependent kinases 2 and 4, bcl-2, while decreased phospho-Akt levels and increased p21, p27, p53 and bax levels and in Bax: Bcl-2 ratio
CycD3↓,
cycE/CCNE↓,
CDK2↓,
CDK4↓,
Bcl-2↓,
P21↑,
p27/CDKN1B↑,
P53↑,
BAX↑,
selectivity↑, lycopene selectively inhibited cell growth in MCF-7 human breast cancer cells but not in the MCF-10 mammary epithelial cells
MMP↓, When treating LNCaP human prostate cancer cells with lycopene, the decreased mitochondrial function could be observed.
Cyt‑c↑, release of mitochondrial cytochrome c and finally led to apoptosis
Wnt↓, Lycopene could inhibit Wnt-TCF signaling pathway in cancer cells.
eff↑, Lycopene could synergistically increase QC anticancer activity and inhibit Wnt-TCF signaling in cancer cells.
PPARγ↑, Lycopene could inhibit the growth of cancer cells by activating the PPARγ – LXRα - ABCA1 pathway and decreasing cellular total cholesterol levels
LDL↓,
Akt↓, Lycopene suppressed Akt activation and non-phosphorylated β-Catenin,
PI3K↓, inhibited the proliferation of colon cancer HT-29 cells, which was associated with suppressing PI3K/Akt/mTOR signaling pathway
mTOR↓,
PDGF↓, Lycopene, however, could inhibit PDGF-BB-induced signaling and cell migration in both human cultured skin fibroblasts and melanoma-derived fibroblasts
NF-kB↓, anticancer properties of lycopene may occur to play its role through the inhibition of the NF-κB signaling pathway
eff↑, lycopene increased the sensitization of cervical cancer cells to cisplatin via the suppression of NF-κB-mediated inflammatory responses, and the modulation of Nrf2-mediated oxidative stress
antiOx↑, Lycopene is a potent antioxidant exhibiting anticancer effects.
AntiCan↑,
ROS↓, results show that lycopene reduced ROS levels and inhibited Jak1/Stat3 activation, alteration of Wnt/β-catenin multiprotein complex molecules, expression of c-Myc and cyclin E, and cell proliferation in H pylori–infected AGS cells.
JAK1↓,
STAT3↓,
Wnt↓,
β-catenin/ZEB1↓,
cMyc↓,
cycE/CCNE↓,
TumCP↓,
Risk↓, Lycopene might be a potential and promising nutrient for preventing H pylori–associated gastric diseases including gastric cancer.
Showing Research Papers: 1 to 50 of 69
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* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 69
Pathway results for Effect on Cancer / Diseased Cells:
Redox & Oxidative Stress(tgid=1) ⓘ
antiOx↓, 1, antiOx↑, 3, ATF3↑, 1, Catalase↑, 1, GPx↑, 2, GSH↓, 1, GSH↑, 2, GSR↑, 2, GSTA1↑, 1, GSTs↝, 1, HO-1↓, 1, HO-1↑, 2, HO-2↓, 1, Keap1↓, 1, lipid-P?, 1, lipid-P↓, 2, lipid-P↑, 1, NQO1↑, 1, NRF2↓, 2, NRF2↑, 4, PARK2↑, 1, ROS↓, 6, ROS↑, 22, mt-ROS↑, 1, SIRT3↑, 2, SOD↑, 1,
Metal & Cofactor Biology(tgid=2) ⓘ
Tf↓, 1,
Mitochondria & Bioenergetics(tgid=3) ⓘ
ADP:ATP↑, 1, AIF↑, 4, ATP↓, 1, CDC2↓, 2, CDC25↓, 2, EGF↓, 1, MEK↓, 1, mitResp↓, 1, MMP↓, 14, mtDam↑, 3, PINK1↑, 1, Raf↓, 2, XIAP↓, 5,
Core Metabolism/Glycolysis(tgid=4) ⓘ
ALAT↓, 1, AMP↓, 1, AMPK↓, 1, AMPK↑, 3, AMPK↝, 1, cMyc↓, 4, CREB↓, 1, ECAR↝, 1, FASN↓, 1, GlucoseCon↓, 2, Glycolysis↓, 3, H2S↑, 1, Histones↑, 1, lactateProd↓, 2, LDHA↓, 1, LDL↓, 2, NADPH↓, 1, NADPH↑, 1, PDK1?, 2, PI3K/Akt↓, 1, PKM2↓, 1, PPARα↓, 1, cl‑PPARα↓, 1, PPARγ↑, 3, p‑S6K↓, 1, SIRT1↓, 2, SIRT1↑, 3, TS↓, 1,
Cell Death(tgid=5) ⓘ
AhR↑, 1, Akt↓, 17, Akt↑, 1, p‑Akt↓, 3, Apoptosis↑, 20, BAD↑, 1, Bak↑, 1, BAX↓, 1, BAX↑, 11, BAX⇅, 1, Bax:Bcl2↑, 6, Bcl-2↓, 13, Bcl-2↑, 1, Bcl-xL↓, 3, BID↑, 1, BIM↑, 1, Casp↑, 6, Casp3↓, 1, Casp3↑, 19, cl‑Casp3↑, 2, Casp7↑, 2, Casp8↑, 10, proCasp8↑, 1, Casp9↑, 14, cl‑Casp9↑, 2, proCasp9↓, 1, Chk2↓, 2, Chk2↑, 2, CK2↓, 1, Cyt‑c↑, 18, Diablo↑, 4, DR4↑, 2, DR5↑, 4, FADD↑, 1, Fas↑, 4, HEY1↓, 1, iNOS↓, 2, JNK↓, 2, JNK↑, 5, MAPK↓, 2, MAPK↑, 2, Mcl-1↓, 8, MDM2↓, 3, MDM2↑, 1, Myc↓, 1, NOXA↑, 1, p27/CDKN1B↓, 1, p27/CDKN1B↑, 18, p38↑, 3, PUMA↑, 1, Pyro↑, 1, survivin↓, 6, Telomerase↓, 4, TRAIL↑, 1, TRPV1↑, 1, TumCD↑, 1,
Kinase & Signal Transduction(tgid=6) ⓘ
p70S6↓, 1, TSC2↑, 1,
Transcription & Epigenetics(tgid=7) ⓘ
cJun↓, 3, EZH2↓, 2, H3↑, 1, HATs↓, 1, pRB↑, 2, tumCV↓, 7,
Protein Folding & ER Stress(tgid=8) ⓘ
CHOP/DDIT3↑, 1, ER Stress↓, 1, ER Stress↑, 9, GRP78/BiP↓, 1, GRP78/BiP↑, 5, HSF1↓, 1, HSP27↓, 1, HSP27↝, 1, HSP70/HSPA5↓, 2, HSP70/HSPA5↝, 1, HSP90↓, 2, IRE1↑, 3, UPR↑, 1,
Autophagy & Lysosomes(tgid=9) ⓘ
ATG5↓, 1, Beclin-1↓, 1, Beclin-1↑, 1, LC3II↓, 1, TumAuto↑, 1, TumAuto⇅, 1,
DNA Damage & Repair(tgid=10) ⓘ
ATM↑, 2, ATR↑, 1, BRCA1↑, 2, BRCA2↑, 1, CHK1↓, 2, CHK1↑, 2, DNAdam↓, 2, DNAdam↑, 11, DNMTs↓, 1, p16↑, 1, P53?, 1, P53↓, 1, P53↑, 16, p‑P53↑, 1, PARP↑, 4, cl‑PARP↓, 1, cl‑PARP↑, 13, PCNA↓, 4, SIRT6↑, 1, TP53↑, 1, γH2AX↓, 1, γH2AX↑, 1,
Cell Cycle & Senescence(tgid=11) ⓘ
CDK1↓, 2, CDK1/2/5/9∅, 1, CDK2↓, 29, CDK2↑, 1, CDK4↓, 34, CDK4↑, 1, cycA1/CCNA1↓, 4, cycA1/CCNA1↑, 1, CycB/CCNB1↓, 2, CycB/CCNB1↑, 2, cycD1/CCND1↓, 41, CycD3↓, 2, cycE/CCNE↓, 50, E2Fs↓, 1, P21↓, 1, P21↑, 32, p‑RB1↓, 5, TumCCA↓, 1, TumCCA↑, 39,
Proliferation, Differentiation & Cell State(tgid=12) ⓘ
CD133↓, 1, CDK8↓, 1, cFos↓, 3, CSCs↓, 3, Diff↓, 1, EMT↓, 9, ERK↓, 6, p‑ERK↓, 2, FOXO↑, 1, FOXO3↑, 1, GSK‐3β↓, 1, HDAC↓, 1, HDAC1↓, 1, HDAC3↓, 1, HH↓, 1, IGF-1↓, 1, Let-7↑, 1, mTOR↓, 9, mTOR↝, 1, p‑mTOR↓, 1, mTORC1↓, 3, p‑mTORC1↓, 1, mTORC2↓, 1, mTORC2↑, 1, n-MYC↓, 1, Nanog↓, 1, Nestin↓, 1, NOTCH↓, 4, OCT4↓, 1, PI3K↓, 11, p‑PI3K↓, 1, PTEN↑, 2, RAS↓, 1, SOX2↓, 2, STAT3↓, 9, p‑STAT3↓, 4, STAT5↓, 1, STAT6↓, 1, TCF-4↓, 2, TOP1↓, 2, TOP2↓, 2, TOP2↑, 1, TumCG↓, 8, tyrosinase↓, 1, Wnt↓, 8, Wnt/(β-catenin)↓, 1,
Migration(tgid=13) ⓘ
AP-1↓, 5, AXL↓, 1, Ca+2↑, 7, Ca+2↝, 1, i-Ca+2↑, 1, CAFs/TAFs↓, 1, Cdc42↑, 1, CDK4/6↓, 1, E-cadherin↓, 1, E-cadherin↑, 4, ER-α36↓, 2, FAK↓, 2, p‑FAK↓, 2, Ki-67↓, 2, miR-200b↑, 1, MMP1↓, 2, MMP2↓, 16, MMP3↓, 1, MMP7↓, 4, MMP9↓, 21, MMPs↓, 6, N-cadherin↓, 3, PDGF↓, 3, PKCδ↓, 2, Slug↓, 2, SMAD3↓, 1, Snail?, 1, Snail↓, 3, TGF-β↓, 5, TIMP2↑, 2, TumCA↓, 1, TumCI↓, 11, TumCMig↓, 11, TumCP↓, 17, TumCP↑, 1, TumCP⇅, 1, TumMeta↓, 8, TumMeta↑, 2, Twist↓, 3, uPA↓, 8, Vim↓, 4, Zeb1↓, 1, ZEB2↓, 1, β-catenin/ZEB1↓, 8,
Angiogenesis & Vasculature(tgid=14) ⓘ
angioG↓, 15, ATF4↑, 4, EGFR↓, 10, Endoglin↑, 1, EPR↑, 1, HIF-1↓, 1, Hif1a↓, 5, NO↓, 1, NO↑, 1, PDGFR-BB↓, 1, p‑PDGFR-BB↓, 1, VEGF↓, 14, VEGFR2/KDR/Flk1↓, 3,
Barriers & Transport(tgid=15) ⓘ
GLUT1↓, 1, NHE1↓, 1, P-gp/ABCB1↓, 2,
Immune & Inflammatory Signaling(tgid=16) ⓘ
CCR7↓, 1, COX1↓, 1, COX2/PTGS2↓, 15, CXCR4↓, 2, IKKα↓, 2, IL1↑, 1, IL1α↓, 1, IL2↑, 1, IL4↓, 1, IL4↑, 1, IL6↓, 3, IL8↓, 2, Inflam↓, 4, JAK↓, 1, JAK1↓, 2, JAK2↓, 3, p‑JAK2↓, 1, M2 MC↓, 1, MCP1/CCL2↓, 2, MIP2↓, 1, NF-kB↓, 20, NF-kB↑, 1, p65↓, 1, PD-L1↓, 1, PGE2↓, 7, PSA↓, 2, TLR4↝, 1, TNF-α↓, 3, TNF-α↑, 1,
Synaptic & Neurotransmission(tgid=18) ⓘ
5HT↓, 1,
Protein Aggregation(tgid=19) ⓘ
NLRP3↑, 1,
Hormonal & Nuclear Receptors(tgid=20) ⓘ
AR↓, 4, CDK6↓, 16, CDK6↑, 2,
Drug Metabolism & Resistance(tgid=21) ⓘ
BioAv↓, 6, BioAv↑, 9, ChemoSen↑, 12, Dose?, 1, Dose↓, 1, Dose↑, 2, Dose↝, 3, Dose∅, 1, eff↓, 3, eff↑, 30, eff↝, 2, Half-Life↓, 2, Half-Life↝, 2, P450↝, 1, RadioS↑, 9, selectivity↑, 14,
Clinical Biomarkers(tgid=22) ⓘ
ALAT↓, 1, ALP↓, 1, AR↓, 4, ascitic↓, 1, AST↓, 1, BRCA1↑, 2, E6↓, 1, E7↓, 1, EGFR↓, 10, EZH2↓, 2, GutMicro↑, 1, IL6↓, 3, Ki-67↓, 2, Myc↓, 1, PD-L1↓, 1, PSA↓, 2, TP53↑, 1,
Functional Outcomes(tgid=23) ⓘ
AntiCan↑, 6, AntiTum↑, 3, chemoPv↑, 4, RenoP↑, 1, Risk↓, 2, toxicity↓, 2, toxicity↑, 1, TumVol↓, 1,
Total Targets: 373
Pathway results for Effect on Normal Cells:
NA, unassigned(tgid=0) ⓘ
AntiBio↑, 1,
Redox & Oxidative Stress(tgid=1) ⓘ
antiOx↓, 1, antiOx↑, 8, Catalase↑, 2, GPx↑, 2, GSH↑, 3, GSR↑, 1, HO-1↑, 2, lipid-P↓, 2, NRF2↑, 3, Prx↑, 1, ROS↓, 5, SOD↑, 2, SOD2↑, 1,
Core Metabolism/Glycolysis(tgid=4) ⓘ
p‑cMyc↑, 1,
Cell Death(tgid=5) ⓘ
Apoptosis↓, 1, Casp3?, 1, iNOS↓, 2, MAPK↑, 1,
Proliferation, Differentiation & Cell State(tgid=12) ⓘ
ERK↑, 1,
Migration(tgid=13) ⓘ
5LO↓, 1, Ca+2↝, 1,
Immune & Inflammatory Signaling(tgid=16) ⓘ
COX2/PTGS2↓, 2, Inflam↓, 7, NF-kB↓, 4, PGE2↓, 1, TNF-α↓, 1,
Synaptic & Neurotransmission(tgid=18) ⓘ
GABA↑, 1,
Protein Aggregation(tgid=19) ⓘ
NLRP3↓, 1,
Drug Metabolism & Resistance(tgid=21) ⓘ
BioAv↓, 3,
Clinical Biomarkers(tgid=22) ⓘ
BP↓, 1, GutMicro↑, 1,
Functional Outcomes(tgid=23) ⓘ
AntiDiabetic↑, 1, cardioP↑, 2, chemoP↑, 1, memory↑, 2, neuroP↑, 2, Obesity↓, 1, Risk↓, 1, toxicity↓, 3, toxicity↑, 2, toxicity∅, 1,
Total Targets: 42
Scientific Paper Hit Count for: cycE/CCNE, Cyclin E
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#:378 State#:% Dir#:1
wNotes=on sortOrder:rid,rpid
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