Fisetin / TumCG Cancer Research Results

FIS, Fisetin: Click to Expand ⟱
Features:
Fisetin is a plant based flavonoid. Found in strawberries(160ug/g), apples, persimmons, onions, cucumbers, grapes.

-Note half-life 3-4hrs
- Oral BioAv low (40-50%)
Pathways:
- induce ROS production in cancer cells, but also known to reduce it.
Also a claim Fisetin-Induced Reactive Oxygen Species Production Has No Effect on Apoptosis in RCC cells
Also one claim (NAC 10-20mM levels) that NAC enhances ROS/apoptosis
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, UPR↑, GRP78↑, Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, HSP↓
- Does not appear to lower antioxidants in cancer cells
- Raises AntiOxidant defense in Normal Cells: ROS↓, NRF2↑, SOD↑, GSH↑, Catalase↑,
- lowers Inflammation : NF-kB↓, COX2↓, p38↓, Pro-Inflammatory Cytokines : IL-1β↓, TNF-α↓, IL-6↓,
- inhibit Growth/Metastases : TumMeta↓, TumCG↓, EMT↓, MMPs↓, MMP2↓, MMP9↓, IGF-1↓, uPA↓, VEGF↓, FAK↓, RhoA↓, NF-κB↓, TGF-β↓, ERK↓
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓, CDK6↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, FAK↓, ERK↓, EMT↓, TOP1↓, TET1↓,
- inhibits HIF-1α↓, cMyc↓, LDH↓, GRP78↑,
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, EGFR↓,
- inhibits Cancer Stem Cells : CD133↓, β-catenin↓,
- Others: PI3K↓, AKT↓, JAK↓, STAT↓, Wnt↓, β-catenin↓, AMPK↓, ERK↓, JNK,
- Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, Others(review target notes), Neuroprotective, Cognitive, Renoprotection, Hepatoprotective, CardioProtective,

- Selectivity: Cancer Cells vs Normal Cells

Fisetin — a naturally occurring plant flavonol and polyphenolic bioactive compound, chemically identified as 3,3′,4′,7-tetrahydroxyflavone. It is classified as a dietary flavonoid, experimental senotherapeutic and preclinical anticancer agent; Fisetin occurs in strawberries, apples, persimmons, grapes, onions and cucumbers, with strawberries providing one of the higher concentrations among commonly consumed foods. Its reported anticancer, neuroprotective and senolytic actions remain predominantly preclinical, and it is not an approved cancer or Alzheimer’s disease therapy.

Primary mechanisms (ranked):

  1. Suppression of PI3K/AKT/mTOR and related survival signaling, reducing tumor-cell proliferation, stress tolerance and treatment resistance.
  2. Induction of intrinsic mitochondrial apoptosis through BAX/Bcl-2 rebalancing, mitochondrial membrane-potential loss, cytochrome-c release and caspase activation.
  3. Inhibition of NF-κB, STAT3 and inflammatory survival transcription, with reductions in COX-2 and tumor-supportive cytokine signaling.
  4. Cell-cycle arrest through reduced cyclin D1, cyclin E, CDK2, CDK4 and CDK6, accompanied in some models by increased p21 or p27.
  5. Suppression of Wnt/β-catenin, EMT, matrix metalloproteinases and focal-adhesion signaling, reducing cancer stemness, migration and invasion.
  6. Biphasic redox modulation: context-dependent ROS elevation and ER or mitochondrial stress in cancer cells, but antioxidant and NRF2-associated cytoprotection in many nonmalignant injury models.
  7. Senotherapeutic activity against selected senescent-cell populations through disruption of senescent-cell anti-apoptotic pathways; selectivity varies markedly by cell type and dosing regimen.
  8. Secondary inhibition of HIF-1α, VEGF and tumor-associated angiogenesis in responsive experimental models.

Bioavailability / PK relevance: Native fisetin has very low aqueous solubility, rapid intestinal and hepatic conjugation, and limited systemic exposure to unconjugated fisetin after conventional oral administration. Glucuronide, sulfate and methylated metabolites can predominate in circulation. Human PK evidence remains limited, although formulated preparations can produce substantially greater exposure than unformulated fisetin. Liposomal, nanoemulsion, phospholipid, cyclodextrin and other delivery systems are therefore mechanistically relevant but cannot be assumed equivalent to ordinary supplements.

In-vitro vs systemic exposure relevance: Many anticancer experiments use approximately 10–100 µM fisetin, commonly 20–80 µM. These concentrations are substantially above the free-parent concentrations expected after ordinary dietary intake and may exceed those produced by conventional oral supplements. Direct translation of cytotoxic concentrations is therefore poor unless tumor accumulation, active metabolites or an exposure-enhancing formulation is demonstrated.

Clinical evidence status: Cancer evidence is predominantly cell-culture and animal evidence. Early human studies are evaluating fisetin as a senolytic or supportive intervention in aging, frailty and cancer-survivor populations, but there is no completed randomized evidence establishing antitumor efficacy. Fisetin should be categorized as preclinical for direct cancer treatment and investigational for adjunct or senotherapeutic use.

Safety / interaction constraints: Food-level exposure is generally regarded as low risk, and small short-term human studies have not identified a clear severe toxicity signal. However, high intermittent senolytic dosing and long-term supplemental dosing remain insufficiently characterized. Mechanistic concerns include antiplatelet or anticoagulant additivity, modulation of drug-metabolizing enzymes and transporters, topoisomerase inhibition, and context-dependent interference with oxidative or cytotoxic cancer treatments. Product purity and formulation-dependent exposure are additional uncertainties.


Fisetin Mechanistic Ranking

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 PI3K AKT mTOR survival signaling ↓ PI3K, ↓ AKT, ↓ mTORC1 and mTORC2 ↔ or adaptive modulation R–G Reduced proliferation and survival A recurrent mechanistic axis across prostate, breast, colorectal, lung and other experimental cancer models.
2 Mitochondrial intrinsic apoptosis ↑ BAX and BIM, ↓ Bcl-2 and Mcl-1, ↓ mitochondrial membrane potential, ↑ cytochrome-c and caspases ↔ generally preserved or protected (model-dependent) R–G Apoptotic tumor-cell death Often downstream of survival-pathway inhibition, ER stress or redox disturbance rather than a single direct mitochondrial target.
3 NF-κB inflammatory survival signaling ↓ IKK and NF-κB activity, ↓ COX-2, ↓ anti-apoptotic transcription ↓ inflammatory NF-κB signaling R–G Reduced inflammation and stress resistance Potentially relevant to both cancer-cell survival and the inflammatory tumor microenvironment.
4 Cell-cycle control ↑ G1 or G2/M arrest, ↓ cyclin D1 and cyclin E, ↓ CDK2, ↓ CDK4 and ↓ CDK6, ↑ p21 or p27 ↔ or transient arrest (context-dependent) G Cytostatic growth suppression The arrest point varies by cancer lineage, genotype, dose and treatment duration.
5 Wnt β-catenin and cancer stemness ↓ Wnt signaling, ↓ β-catenin, ↓ CD44 and CD133 (model-dependent) ↔ G Reduced stem-like phenotype and tumor propagation Particularly relevant in colorectal and other tumors with active Wnt or β-catenin signaling.
6 EMT focal adhesion and matrix degradation ↓ EMT, ↓ FAK, ↓ RhoA and uPA, ↓ MMP-2 and MMP-9, ↑ E-cadherin ↔ G Reduced migration, invasion and metastasis Primarily preclinical phenotype data; suppression of several nodes is model-dependent.
7 ER stress and unfolded protein response ↑ PERK, ↑ eIF2α, ↑ ATF4 and CHOP, ↑ GRP78 or BiP (context-dependent) ↔ or ↓ pathological ER stress R–G Stress-mediated apoptosis GRP78 induction may indicate stress activation rather than beneficial suppression; prolonged CHOP signaling favors death.
8 Mitochondrial ROS increase ↑ ROS and mtROS (dose-dependent), but ↓ or neutral ROS in some models ↓ ROS in oxidative-injury models P–R Biphasic redox modulation ROS elevation is not universal or necessarily required for apoptosis. Direction depends on concentration, cell type and baseline oxidative state.
9 NRF2 antioxidant response ↑ or ↓ NRF2 (context-dependent) ↑ NRF2, ↑ HO-1, ↑ GSH, ↑ SOD and catalase R–G Adaptive antioxidant regulation Predominantly protective in normal-tissue injury models; tumor-cell NRF2 activation could theoretically reduce treatment sensitivity.
10 Calcium ER mitochondrial stress ↑ cytosolic Ca²⁺ (model-dependent) ↔ P–R Amplification of ER and mitochondrial apoptosis Documented in selected models and should not be treated as a universal primary mechanism.
11 HIF-1α VEGF angiogenic signaling ↓ HIF-1α, ↓ VEGF and ↓ angiogenesis ↔ or vascular protection (injury-dependent) G Reduced hypoxic adaptation and neovascularization Evidence is preclinical and is not equivalent to clinically validated antiangiogenic activity.
12 Glycolysis and metabolic adaptation ↓ HIF-1α, ↓ c-Myc and altered LDH or glycolytic activity (model-dependent) ↔ G Reduced metabolic flexibility The database claim that fisetin uniformly inhibits glycolysis is too broad; direct evidence for comprehensive HK2, GLUT1, PKM2 and LDHA suppression is not consistent across models.
13 Senescent-cell survival networks ↓ survival of selected senescent tumor or stromal cells ↓ senescent-cell burden while sparing many nonsenescent cells (model-dependent) G Senolytic or senomorphic activity Activity is heterogeneous and cannot be generalized to every senescent cell type. Effects on therapy-induced tumor senescence may be beneficial or contextually complex.
14 Chemosensitization and radiosensitization ↑ treatment response through ↓ AKT, ↓ NF-κB, apoptosis priming and possible DNA-damage enhancement ↔ or tissue protection (agent-dependent) R–G Potential adjunct sensitization Preclinical only. Antioxidant effects in normal or tumor cells create treatment-specific uncertainty and require schedule-dependent evaluation.
15 Clinical Translation Constraint Common effective in-vitro concentrations exceed ordinary systemic free-fisetin exposure Human high-dose and long-term safety remain incompletely defined G Limited clinical translatability Poor solubility, rapid conjugation, formulation dependence, tumor heterogeneity, uncertain active-metabolite contribution and absence of established anticancer efficacy are major constraints.

P: 0–30 min    R: 30 min–3 hr    G: >3 hr



Alzheimer’s disease relevance: Fisetin has significant but predominantly preclinical relevance to Alzheimer’s disease and related neurodegenerative disorders. Experimental studies report preservation of synaptic function and cognition, suppression of microglial inflammatory signaling, reduction of oxidative stress, promotion of autophagic clearance of phosphorylated tau, and modulation of amyloid-associated toxicity. Senescent-cell clearance provides an additional emerging rationale, but the relative contribution of senolysis versus direct neuroprotective signaling is unresolved. A pilot clinical study in mild cognitive impairment or mild Alzheimer’s disease is registered, but no completed trial currently establishes cognitive efficacy.

Exposure constraint: Most neurological evidence comes from cell and animal models. Native fisetin’s poor solubility, rapid conjugation and uncertain free-brain exposure materially limit direct translation. CMS121 and other fisetin-derived compounds are being developed partly to improve potency, metabolic stability and neuroprotective exposure.

Fisetin in Alzheimer’s Disease

Rank Pathway / Axis Modulation TSF Primary Effect Notes / Interpretation
1 Neuroinflammation and microglial activation ↓ NF-κB, ↓ inflammatory microglial activation, ↓ pro-inflammatory mediators R–G Reduced chronic neuroinflammatory stress One of the more consistent neuroprotective mechanisms in cellular and animal models.
2 Synaptic plasticity and ERK CREB signaling ↑ ERK-dependent synaptic signaling and long-term potentiation (context-dependent) R–G Preservation of learning and memory Neuronal ERK activation differs from the ERK suppression reported in many cancer models.
3 Tau autophagic clearance ↑ TFEB and autophagic processing, ↓ phosphorylated tau accumulation G Improved proteostasis Demonstrated preclinically; human relevance and required brain exposure remain unknown.
4 Amyloid β toxicity and aggregation ↓ amyloid-associated oxidative injury and fibril formation (model-dependent) G Reduced amyloid-mediated neuronal stress Evidence does not establish clinically meaningful plaque removal.
5 NRF2 antioxidant defense ↑ NRF2, ↑ HO-1 and endogenous antioxidant capacity R–G Protection from oxidative neuronal injury Protective signaling may cooperate with TFEB-mediated proteostasis.
6 Neuronal mitochondria and apoptosis ↓ mitochondrial dysfunction, ↓ ROS and ↓ apoptotic signaling R–G Improved neuronal survival Direction is opposite to the pro-oxidant mitochondrial stress sought in many cancer models.
7 Cellular senescence and SASP ↓ selected senescent-cell burden and ↓ senescence-associated inflammatory signaling G Potential reduction of age-related neuroinflammation Mechanistically plausible but not yet clinically validated in Alzheimer’s disease.
8 Clinical Translation Constraint Limited and formulation-dependent systemic and brain exposure; no established therapeutic dose G Uncertain human efficacy Registered pilot testing does not yet constitute efficacy evidence. Native fisetin may not reproduce the exposure or pharmacology of optimized derivatives.

P: 0–30 min    R: 30 min–3 hr    G: >3 hr
TumCG, Tumor cell growth: Click to Expand ⟱
Source:
Type:
Normal cells grow and divide in a regulated manner through the cell cycle, which consists of phases (G1, S, G2, and M).
Cancer cells often bypass these regulatory mechanisms, leading to uncontrolled proliferation. This can result from mutations in genes that control the cell cycle, such as oncogenes (which promote cell division) and tumor suppressor genes (which inhibit cell division).
Scientific Papers found: Click to Expand⟱
6898- FIS,    Fisetin induces autophagic cell death through suppression of mTOR signaling pathway in prostate cancer cells
- in-vitro, Pca, PC3 - in-vitro, Pca, DU145 - in-vitro, Pca, LNCaP
mTOR↓, we show that the treatment of androgen-independent and PTEN-negative human CaP PC3 cells with fisetin, a dietary flavonoid, resulted in inhibition of mTOR kinase signaling pathway
Akt↓, inhibition of Akt and activation of AMPK.
AMPK↑,
TumCG↓, Fisetin induces growth inhibition of PC3 CaP cells and decreases the activity of mTOR kinase
mTORC1↓, Fisetin inhibits phosphorylation of mTOR and expression of the mTORC1 and mTORC2 constituents
mTORC2↓,
4E-BP1↑, Fisetin dephosphorylates and activates 4EBP1, the inhibitor of Cap-dependent translation
LC3II↑, Fisetin induces LC3 II protein expression
TumAuto↑, Fisetin induces autophagy and CQ attenuates the effect of fisetin in PC3 cells

6906- FIS,  Rad,    Combining fisetin and ionizing radiation suppresses the growth of mammalian colorectal cancers in xenograft tumor models
- in-vivo, CRC, CT26 - in-vivo, CRC, HCT116
antiOx↑, activities in human cancer cells, including antioxidant, anti-inflammatory, antiangiogenic, anti-invasive and antiproliferative effects.
Inflam↓,
angioG↓,
TumCI↓,
TumCP↓,
TumCG↓, intratumoral injection of fisetin significantly suppressed the growth of CT-26 tumors compared with the untreated control group, but had little effect on the growth of HCT116 tumors.
RadioS↑, However, fisetin in combination with 2-Gy radiation enhanced tumor suppressor activity in murine colon and human colorectal xenograft tumors, as compared with 2-Gy fractionated radiation administered alone for 5 days and fisetin alone.

6901- FIS,    Fisetin induces G2/M phase arrest and caspase-mediated cleavage of p21Cip1 and p27Kip1 leading to apoptosis and tumor growth inhibition in HNSCC
- in-vivo, HNSCC, CAL33
TumCG↓, fisetin (25-75 µM for 24-48 h) dose-dependently inhibited growth and induced death in HNSCC Cal33 and UM-SCC-22B cells
TumCD↑,
selectivity↑, without showing any death in normal cells
TumCCA↑, Fisetin (25-50 µM) induced G2/M phase arrest via decrease in Cdc25C, CDK1, cyclin B1 expression, and an increase in p53(
CDC25↓,
CDK1↓,
CycB/CCNB1↓,
P53↑,
DNAdam↑, concentration-dependent increase in fisetin-induced DNA damage and apoptosis in HNSCC cells was authenticated by comet assay, gamma-H2A.X
Apoptosis↑,
γH2AX↑,
cl‑PARP↑, marked cleavage of PARP protein
other↝, Interestingly, fisetin-induced cell death occurred independently of p53 and reactive oxygen species production.
JNK↑, activation of JNK and inhibition of PI3K/Akt, ERK1/2, EGFR, and STAT-3 signaling were identified.
PI3K↓,
Akt↓,
ERK↓,
EGFR↓,
STAT3↓,
TumAuto↑, fisetin was also found to induce autophagy; nevertheless, autophagy attenuation exaggerated apoptosis.
Dose↝, Oral fisetin (50 mg/kg body weight) treatment to establish Cal33 xenograft in mice for 19 days showed 73% inhibition in tumor volume (p < 0.01) along with a decrease in Ki67-positive cells and an increase in cleaved caspase-3 level in tumors.
TumVol↓,
Ki-67↓,
cl‑Casp3↑,
P21↓, protein levels of p21Cip1 and P27Kip1 were also decreased by fisetin in tumors.
p27/CDKN1B↓,

6897- FIS,    Fisetin: A Dietary Antioxidant for Health Promotion
- Review, Nor, NA
*chemoPv↑, Fisetin has been reported as a chemopreventive/chemotherapeutic agent in several types of cancer and also as a neuroprotective agent.
*neuroP↑,
*antiOx↑, Several studies indicate that fisetin is a promising novel antioxidant. The trolox-equivalent activity concentration (TEAC) value of fisetin has been reported to be 2.80±0.06 (
*GSH↑, Fisetin has been shown to increase intracellular glutathione (GSH) levels in the mouse hippocampal HT-22 cells both in the presence and absence of glutamate
*HO-1↑, the effect of fisetin on the upregulation of heme oxygenase-1 (HO-1)
*NRF2↑, Treatment with fisetin caused increased Nrf2 nuclear translocation and activity.
angioG↓, fisetin may reduce angiogenesis and consequently suppress tumor growth through inhibition of urokinase plasminogen activator (uPA)
TumCG↓,
uPA↓,
MMP1↓, fisetin to be a potent inhibitor of the matrix metalloproteinase (MMP)-1 activity
tumCV↓, Lung Decreased cancer cell viability and clonogenecity, increased PTEN, decreased PI3-K and Akt phosphorylation, activated TSC and AMPK, decreased phosphorylation and activation of mTOR,
PTEN↑,
PI3K↓, Fisetin also acts as a dual inhibitor of PI3K/Akt and mTOR signaling in prostate cancer cells
p‑Akt↓,
AMPK↑,
mTOR↓,
EGFR↓, Inhibited EGFR and NF-κB, decreased COX2 and PGE2, inhibited Wnt/β-catenin signaling, downregulated TCF-4, decreased cyclin D1 and MMP-7
NF-kB↓,
COX2/PTGS2↓,
PGE2↓,
Wnt↓,
β-catenin/ZEB1↓,
TCF↓,
cycD1/CCND1↓,
MMP7↓,
RadioS↑, Enhanced radiosensitivity of p53-mutant colon cancer cells, augmented radiation-induced G2/M arrest and apoptosis
PSA↓, Prostate Slowed tumor growth, decreased serum PSA levels
Securin↓, Moreover, fisetin inhibited securin expression regardless of p53 status,
TumCCA↑, accompanied by arrest of cells in the G0/G1 phase of the cell cycle
XIAP↓, fisetin treatment resulted in a decrease in the activity of NF-κB/p65, MMP-9, and X-linked inhibitor of apoptosis (XIAP)
*ERK↑, fisetin was the most effective flavonoid that induced neurite outgrowth by inducing ERK1/2 activation
*p‑CREB↑, Fisetin activated ERK1/2 and induced cAMP-response element-binding protein (CREB) phosphorylation in rat hippocampal slices and enhanced object recognition in mice.
*memory↑,
*GSH↑, It acts as an antioxidant, increases GSH, maintains mitochondrial function in the presence of oxidative stress, has anti-inflammatory activity against microglial cells, and inhibits the activity of 5-lipoxygenase,
*Inflam↓,
*5LO↓,

6994- FIS,    Fisetin inhibits the activities of cyclin-dependent kinases leading to cell cycle arrest in HT-29 human colon cancer cells
- in-vitro, Colon, HT29
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↑,

2830- FIS,    Biological effects and mechanisms of fisetin in cancer: a promising anti-cancer agent
- Review, Var, NA
TumCG↓, suppressing cell growth, triggering programmed cell death, reducing the formation of new blood vessels, protecting against oxidative stress, and inhibiting cell migration.
angioG↓,
*ROS↓,
TumCMig↓,
VEGF↓, including vascular endothelial growth factor (VEGF), mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), PI3K/Akt/mTOR, and Nrf2/HO-1.
MAPK↑, including the activation of MAPK. activation of MAPK is crucial for mediating cancer cell proliferation, apoptosis, and invasion
NF-kB↓, ability of fisetin to suppress NF-κB activity has been demonstrated in various diseases
PI3K↓, fisetin has been shown to inhibit the metastasis of PC3 prostate cancer cells by reducing the activity of the PI3K/AKT
Akt↓,
mTOR↓, Fisetin has been shown to be effective against PI3K expression, AKT phosphorylation, and mTOR activation in various cancer cells,
NRF2↑, effects of fisetin on the activation of Nrf2 and upregulation of HO-1 have been demonstrated in various diseases
HO-1↑,
ROS↓, Liver cancer Resist proliferation, migration and invasion, induce apoptosis, attenuate ROS and inflammation
Inflam↓,
ER Stress↑, Oral cancer Induce apoptosis and autophagy, promote ER stress and ROS, suppress proliferation
ROS↑, Multiple studies have demonstrated that fisetin has the ability to induce apoptosis in cancer cells, and various mechanisms are involved, including the activation of MAPK, NF-κB, p53, and the generation of reactive oxygen species (ROS)
TumCP↓,
ChemoSen↑, Breast cancer Promote apoptosis and invasion and metastasis, enhance chemotherapeutic effects
PTEN↑,
P53↑, activation of MAPK, NF-κB, p53,
Casp3↑,
Casp8↑,
Casp9↑,
COX2/PTGS2↓, fisetin inhibits COX2 expression
Wnt↓, regulating a number of important angiogenesis-related factors in cancer cells, such as VEGF, MMP2/9, eNOS, wingless and Wnt-signaling.
EGFR↓,
Mcl-1↓,
survivin↓, fisetin interferes with NF-κB signaling, resulting in the reduction of survivin, TRAF1, Bcl-xl, Bcl-2, and IAP1/2 levels, ultimately inhibiting apoptosis
IAP1↓,
IAP2/BIRC3↓,
PGE2↓, fisetin inhibits COX2 expression, leading to the down-regulation of PGE2 secretion and inactivation of β-catenin, thereby inducing apoptosis
β-catenin/ZEB1↓,
DR5↑, fisetin markedly induces apoptosis in renal carcinoma through increased expression of DR5, which is regulated by p53.
MMP2↓, fisetin has been shown to inhibit the metastasis of PC3 prostate cancer cells by reducing the activity of the PI3K/AKT and JNK pathways, resulting in the suppression of MMP-2 and MMP-9 expression
MMP9↓,
FAK↓, fisetin can inhibit cell migration and reduce focal adhesion kinase (FAK) phosphorylation levels
uPA↓, fisetin significantly suppresses the invasion of U-2 cells by decreasing the expression of NF-κB, urokinase-type plasminogen activator (uPA), FAK, and MMP-2/9
EMT↓, Fisetin has been shown to have the ability to reverse EMT, thereby inhibiting the invasion and migration of cancer cells
ERK↓, fisetin has the ability to suppress ERK1/2 activation and activate JNK/p38 pathways
JNK↑,
p38↑,
PKCδ↓, fisetin reduces the expression of MMP-9 by inhibiting PKCα/ROS/ERK1/2 and p38 MAPK activation
BioAv↓, low water solubility of fisetin poses a significant challenge for its administration, which can limit its biological effects
BioAv↑, Compared to free fisetin, fisetin nanoemulsion has demonstrated a 3.9-fold increase in the generation of reactive oxygen species (ROS) and induction of apoptosis, highlighting its enhanced efficacy
BioAv↑, Liposomal encapsulation has shown potential in enhancing the anticancer therapeutic effects of fisetin

2839- FIS,    Dietary flavonoid fisetin for cancer prevention and treatment
- Review, Var, NA
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

2831- FIS,    Fisetin as a chemoprotective and chemotherapeutic agent: mechanistic insights and future directions in cancer therapy
- Review, Var, NA
TumCG↓, Fisetin has shown the ability to suppress tumor growth and metastasis by modulating critical signaling pathways, including PI3K/Akt/mTOR, NF-κB, and MAPK.
ER Stress↑, It induces apoptosis in cancer cells through mitochondrial and endoplasmic reticulum stress responses and demonstrates antioxidative properties by reducing reactive oxygen species.
antiOx↓,
ROS↓,
ChemoSen↑, Additionally, fisetin enhances the efficacy of conventional chemotherapies, indicating its role as a potential adjuvant in cancer treatment.

2829- FIS,    Fisetin: An anticancer perspective
- Review, Var, NA
TumCP↓, Being a potent anticancer agent, fisetin has been used to inhibit stages in the cancer cells (proliferation, invasion), prevent cell cycle progression, inhibit cell growth, induce apoptosis, cause polymerase (PARP) cleavage
TumCI↓,
TumCCA↑,
TumCG↓,
Apoptosis↑,
cl‑PARP↑,
PKCδ↓, fisetin also suppresses the activation of the PKCα/ROS/ERK1/2 and p38 MAPK signaling pathways, reduces the NF‐κB activation, and down‐regulates the level of the oncoprotein securin
ROS↓,
ERK↓,
NF-kB↓,
survivin↓,
ROS↑, In human multiple myeloma U266 cells, fisetin stimulated the production of free radical species that led to apoptosis
PI3K↓, Multiple studies also authenticated the anticancer role of fisetin through various signaling pathways such as blocking of mammalian target of rapamycin (PI3K/Akt/mTOR)
Akt↓,
mTOR↓,
MAPK↓, phosphatidylinositol‐3‐kinase/protein kinase B, mitogen‐activated protein kinases (MAPK)‐dependent nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB), and p38, respectively,
p38↓,
HER2/EBBR2↓, (HER2)/neu‐overexpressing breast cancer cell lines. Fisetin caused induction through inactivating the receptor, inducing the degradation of the proteasomes, reducing its half‐life
EMT↓, In addition, mutation of epithelial‐to‐mesenchymal transition (EMT)
PTEN↑, up‐regulation of expression of PTEN mRNA and protein were reported after fisetin treatment
HO-1↑, In breast cancer cells (4T1 and JC cells), fisetin increased HO‐1 mRNA and protein expressions, elevated Nrf2 expression
NRF2↑,
MMP2↓, fisetin reduced MMP‐2 and MMP‐9 enzyme activity and gene expression for both mRNA levels and protein
MMP9↓,
MMP↓, fisetin treatment further led to permeabilization of mitochondrial membrane, activation of caspase‐8 and caspase‐9, as well as the cleavage of poly(ADP‐ribose) polymerase 1
Casp8↑,
Casp9↑,
TRAILR↑, enhanced the levels of TRAIL‐R1
Cyt‑c↑, mitochondrial releasing of cytochrome c into cytosol, up‐regulation and down‐regulation of X‐linked inhibitor of apoptosis protein
XIAP↓,
P53↑, fisetin also enhanced the protein p53 levels
CDK2↓, lowered cell number, the activities of CDK‐2,4)
CDK4↓,
CDC25↓, it also decreased cell division cycle protein levels (CDC)2 and CDC25C, and CDC2 activity (Lu et al., 2005)
CDC2↓,
VEGF↓, down‐regulating the expressions of p‐ERK1/2, vascular endothelial growth factor receptor 1(VEGFR1), p38, and pJNK, respectively
DNAdam↑, Fisetin (80 microM) showed dose‐dependently caused DNA fragmentation, induced cellular swelling and apoptotic death, and showed characteristics of apoptosis.
TET1↓, lowered the TET1 expression levels
CHOP/DDIT3↑, caused up‐regulation of (C/EBP) homologous protein (CHOP) expression and reactive oxygen species production,
CD44↓, down‐regulation of CD44 and CD133 markers
CD133↓,
uPA↓, down‐regulation of levels of matrix metalloproteinase‐2 (MMP‐2), urokinase‐type plasminogen activator (uPA),
CSCs↓, Being a potent anticancer agent, fisetin administration in in vitro and in vivo studies in kidney renal stem cells (HuRCSCs) effectively inhibited cancer cell stages such as proliferation,

2859- FIS,    The Natural Flavonoid Fisetin Inhibits Cellular Proliferation of Hepatic, Colorectal, and Pancreatic Cancer Cells through Modulation of Multiple Signaling Pathways
- in-vitro, Liver, HepG2 - NA, Colon, Caco-2
TumCG↓, fisetin induces growth inhibition, and apoptosis in hepatic (HepG-2), colorectal (Caco-2) and pancreatic (Suit-2) cancer cell lines.
other↝, activation of CDKN1A, SEMA3E, GADD45B and GADD45A and down-regulation of TOP2A, KIF20A, CCNB2 and CCNB1 genes.
Casp3↑, Fisetin caused significant increase in activation of caspase 3/7 compared to untreated control
Casp7↑,
PGE2↓, Fisetin inhibits PGE2 production
GSTs↓, GST enzyme activity assay has been carried out. The results showed that fisetin induced enzyme inhibition in a dose dependent manner
Wnt↓, inhibiting Wnt/EGFR/NF-kB and COX-2 signaling pathways
EGFR↓,
NF-kB↓,
COX2/PTGS2↓,
P53↑, induction of p53 and p21
P21↑,
P450↓, Fisetin also was able to inhibit cyctochrome P450 (CYP450 3A4) and glutatihione -S-transferase activity


Showing Research Papers: 1 to 10 of 10

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 10

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

antiOx↓, 1,   antiOx↑, 1,   GSTs↓, 1,   HO-1↑, 2,   lipid-P↓, 1,   NRF2↑, 2,   ROS↓, 4,   ROS↑, 3,  

Mitochondria & Bioenergetics(tgid=3) ⓘ

CDC2↓, 1,   CDC25↓, 2,   EGF↓, 1,   MMP↓, 1,   XIAP↓, 2,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

AMPK↑, 2,  

Cell Death(tgid=5) ⓘ

Akt↓, 5,   p‑Akt↓, 1,   Apoptosis↑, 3,   BAX↑, 1,   Bcl-2↓, 1,   Casp3↑, 2,   cl‑Casp3↑, 2,   Casp7↑, 1,   Casp8↑, 2,   Casp9↑, 2,   cl‑Casp9↑, 1,   Cyt‑c↑, 2,   DR5↑, 1,   IAP1↓, 1,   IAP2/BIRC3↓, 1,   JNK↑, 2,   MAPK↓, 1,   MAPK↑, 1,   Mcl-1↓, 1,   p27/CDKN1B↓, 1,   p38↓, 1,   p38↑, 1,   survivin↓, 2,   TRAILR↑, 1,   TumCD↑, 1,  

Kinase & Signal Transduction(tgid=6) ⓘ

HER2/EBBR2↓, 1,   TSC2↑, 1,  

Transcription & Epigenetics(tgid=7) ⓘ

cJun↓, 1,   other↝, 2,   tumCV↓, 1,  

Protein Folding & ER Stress(tgid=8) ⓘ

CHOP/DDIT3↑, 1,   ER Stress↑, 3,   GRP78/BiP↑, 1,   IRE1↑, 1,  

Autophagy & Lysosomes(tgid=9) ⓘ

LC3II↑, 1,   TumAuto↑, 2,  

DNA Damage & Repair(tgid=10) ⓘ

DNAdam↑, 3,   P53↑, 4,   cl‑PARP↑, 2,   γH2AX↑, 1,  

Cell Cycle & Senescence(tgid=11) ⓘ

CDK1↓, 1,   CDK2↓, 3,   CDK4↓, 3,   CycB/CCNB1↓, 1,   cycD1/CCND1↓, 3,   cycE/CCNE↓, 2,   P21↓, 1,   P21↑, 3,   Securin↓, 1,   TumCCA↑, 5,  

Proliferation, Differentiation & Cell State(tgid=12) ⓘ

4E-BP1↑, 1,   CD133↓, 1,   CD44↓, 1,   cFos↓, 1,   CSCs↓, 1,   EMT↓, 3,   ERK↓, 4,   mTOR↓, 5,   mTORC1↓, 2,   mTORC2↓, 2,   PI3K↓, 5,   PTEN↑, 3,   STAT3↓, 1,   TCF↓, 1,   TCF-4↓, 1,   TumCG↓, 10,   Wnt↓, 4,  

Migration(tgid=13) ⓘ

AP-1↓, 1,   FAK↓, 1,   Ki-67↓, 1,   MMP1↓, 1,   MMP2↓, 2,   MMP7↓, 2,   MMP9↓, 3,   PKCδ↓, 2,   TET1↓, 1,   TGF-β↓, 1,   TumCA↓, 1,   TumCI↓, 3,   TumCMig↓, 2,   TumCP↓, 3,   uPA↓, 4,   β-catenin/ZEB1↓, 3,  

Angiogenesis & Vasculature(tgid=14) ⓘ

angioG↓, 3,   ATF4↑, 1,   EGFR↓, 5,   VEGF↓, 2,  

Barriers & Transport(tgid=15) ⓘ

P-gp/ABCB1↓, 1,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

COX2/PTGS2↓, 4,   Inflam↓, 2,   NF-kB↓, 5,   PGE2↓, 3,   PSA↓, 1,  

Hormonal & Nuclear Receptors(tgid=20) ⓘ

AR↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

BioAv↓, 1,   BioAv↑, 2,   ChemoSen↑, 3,   Dose↝, 1,   eff↑, 2,   P450↓, 1,   RadioS↑, 3,   selectivity↑, 1,  

Clinical Biomarkers(tgid=22) ⓘ

AR↓, 1,   EGFR↓, 5,   HER2/EBBR2↓, 1,   Ki-67↓, 1,   PSA↓, 1,  

Functional Outcomes(tgid=23) ⓘ

TumVol↓, 1,  
Total Targets: 122

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

antiOx↑, 1,   GSH↑, 2,   HO-1↑, 1,   NRF2↑, 1,   ROS↓, 1,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

p‑CREB↑, 1,  

Proliferation, Differentiation & Cell State(tgid=12) ⓘ

ERK↑, 1,  

Migration(tgid=13) ⓘ

5LO↓, 1,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

Inflam↓, 1,  

Functional Outcomes(tgid=23) ⓘ

chemoPv↑, 1,   memory↑, 1,   neuroP↑, 1,  
Total Targets: 12

Scientific Paper Hit Count for: TumCG, Tumor cell growth
10 Fisetin
1 Radiotherapy/Radiation
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#:78  Target#:323  State#:%  Dir#:%
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