Fisetin 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">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
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.

6905- FIS,    Fisetin overcomes non-targetability of mutated KRAS induced YB-1 signaling in colorectal cancer cells and improves radiosensitivity by blocking repair of radiation-induced DNA double-strand breaks
- in-vitro, CRC, NA
RadioS↑, Combination of fisetin with radiotherapy may improve CRC radiation response, regardless of KRASmut status.

6904- FIS,    Fisetin Inhibits Migration and Invasion of Human Cervical Cancer Cells by Down-Regulating Urokinase Plasminogen Activator Expression through Suppressing the p38 MAPK-Dependent NF-κB Signaling Pathway
- in-vitro, Cerv, NA
TumCP↓, Fisetin (3,3’,4’,7-tetrahydroxyflavone), a naturally occurring flavonoid, has been reported to inhibit proliferation and induce apoptosis in several cancer types.
Apoptosis↑,
TumCI↓, In the present study, we found that fisetin inhibits the invasion and migration of cervical cancer cells.
TumCMig↓,
uPA↓, urokinase plasminogen activator (uPA) was significantly suppressed by fisetin in a dose-dependent manner.

6903- FIS,    Involvement of the ERK signaling pathway in fisetin reduces invasion and migration in the human lung cancer cell line A549
- in-vitro, Lung, A549
TumCMig↓, Fisetin exhibited an inhibitory effect on the abilities of adhesion, migration, and invasion via inhibiting the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and downregulating the expressions of matrix metalloproteinase-2
TumCI↓,
ERK↓,
MMP2↓,
uPA↓, and urokinase-type plasminogen activator (u-PA) at both the protein and mRNA levels in A549 cells.
NF-kB↓, fisetin significantly decreased the nuclear levels of nuclear factor kappa B (NF-kappaB), c-Fos, and c-Jun.
cFos↓,
cJun↓,

6902- FIS,    Fisetin, a dietary flavonoid, induces cell cycle arrest and apoptosis through activation of p53 and inhibition of NF-kappa B pathways in bladder cancer cells
- in-vitro, Bladder, T24/HTB-9
P53↑, we report that fisetin-induced apoptosis in human bladder cancer is mediated via modulation of two related pathways: up-regulation of p53 and down-regulation of NF-kappa B activity,
NF-kB↓,
TumCP↓, fisetin inhibited the proliferation of T24 and EJ cells by inducing apoptosis and blocking cell cycle progression in the G0/G1 phase.
Apoptosis↑,
TumCCA↑,
P21↑, fisetin significantly increases the expression of p53 and p21 proteins, and decreases the levels of cyclin D1, cyclin A, CDK4 and CDK2, thereby contributing to cell cycle arrest.
cycD1/CCND1↓,
cycA1/CCNA1↓,
CDK4↓,
CDK2↓,
BAX↑, fisetin increased the expression of Bax and Bak but decreased the levels of Bcl-2 and Bcl-xL and subsequently triggered mitochondrial apoptotic pathway
Bak↑,
Bcl-2↓,
Bcl-xL↓,

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↓,

6900- FIS,    Fisetin targets phosphatidylinositol-3-kinase and induces apoptosis of human B lymphoma Raji cells
- in-vitro, lymphoma, NA
PI3K↓, Fisetin inhibits PI3K activity at the enzymatic and cellular levels.
Apoptosis↑, Fisetin induces the apoptosis of Raji cells by downregulating cIAP-2 protein expression.
IAP2/BIRC3↓,
mTOR↓, Fisetin inhibits mTOR activity
γH2AX↑, The levels of γH2A.X protein increased over time in the presence of 30 μM fisetin (Fig. 3), suggesting the involvement of DNA damage
DNAdam↑,

6899- FIS,    Fisetin, a novel dietary flavonoid, causes apoptosis and cell cycle arrest in human prostate cancer LNCaP cells
- in-vitro, Pca, LNCaP - in-vitro, Pca, PC3 - in-vitro, Pca, 22Rv1
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↓,

6907- FIS,    Fisetin stimulates autophagic degradation of phosphorylated tau via the activation of TFEB and Nrf2 transcription factors
- in-vitro, AD, NA
*p‑tau↓, Treatment of cortical cells or primary neurons with fisetin resulted in significant decreases in the levels of phosphorylated tau.
*NRF2↑, Fisetin activated autophagy together with the activation of transcription factor EB (TFEB) and Nrf2 transcriptional factors
*mTORC1↓, fisetin-mediated mammalian target of rapamycin complex 1 (mTORC1) inhibition
*neuroP↑, fisetin showed neurotrophic activity distinct from other flavonoids, and exhibited the most potent, neuroprotective effects8
*memory↑, and promotes memory in wild type mice9
*Inflam↓, fisetin also has a strong anti-inflammatory activity in brain
*memory↑, and its oral administration significantly attenuated the development of learning and memory deficits in an AD mouse model1
*TFEB↑, Fisetin activates TFEB
*mTOR↓, Fisetin inhibits mTOR.

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↓,

6896- FIS,    Fisetin is a senotherapeutic that extends health and lifespan
- in-vivo, Nor, NA
*AntiAge↑, Administration of fisetin to wild-type mice late in life restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan.
*cellSen↑, Of the 10 flavonoids tested, fisetin was the most potent senolytic
*selectivity⇅, Fisetin reduced senescence in a subset of cells in murine and human adipose tissue, demonstrating cell-type specificity.

6895- FIS,    Enhanced bioavailability and pharmacokinetics of a novel hybrid-hydrogel formulation of fisetin orally administered in healthy individuals: a randomised double-blinded comparative crossover study
- in-vivo, Nor, NA
*neuroP↑, many pre-clinical studies for neuroprotection, cardioprotection, chemoprevention, diabetes, inflammation and oxidative stress.
*cardioP↑,
*chemoPv↑,
*AntiDiabetic↑,
*Inflam↓,
*ROS↓,
*BioAv↓, clinical effectiveness of fisetin may be limited by its poor bioavailability when ingested.
*BioAv↑, food-grade fisetin formulation (FF-20) was developed through encapsulation of fisetin micelles into fenugreek galactomannan (FG) hydrogel scaffold to improve its physical characteristics and bioavailability.
*eff↑, concentration of fisetin when individuals consumed FF-20 was 26⋅9-fold greater than UF as determined by the area under the curve over 12 h
*Half-Life↓, The serum levels of free fisetin declined within minutes following intravenous administration (t1/2 = 2⋅7 min) and were only barely quantifiable in very limited samples up to 90 min following oral administration

5392- FIS,  AsP,    Fisetin topical delivery via ascorbyl palmitate/hyaluronan-enhanced limosomes: a novel paradigm for preventing UVB-induced skin photoaging
- in-vivo, Nor, NA
eff↑, Due to FIS’s poor solubility and high lipophilicity, it was encapsulated in D-limonene-modified phospholipid carriers, limosomes (LIMOs), co-formulated with Ascorbyl Palmitate (AP) and Hyaluronan (HYA) to improve FIS’s solubility, skin penetration, a
*antiOx↑, FIS-AP-HYA-LIMOs showed potent in vitro antioxidant activity, high biocompatibility, and remained stable for 6 months.
*MMP9↓, In vivo studies revealed the downregulation of MMP9, TNFα, and NF-κB, accompanied by increased SOD and CAT levels, indicating superior anti-ageing, anti-inflammatory, and antioxidant effects compared to FIS suspension
*TNF-α↓,
*NF-kB↓,
*SOD↑,
*Catalase↑,
*AntiAge↑,
*Inflam↓,
*JNK↓, AP-HYA-LIMOs decreased JNK expression, preserved the integrity of skin layers, and reduced collagen degradation.

2862- FIS,    Fisetin averts oxidative stress in pancreatic tissues of streptozotocin-induced diabetic rat
- in-vivo, Diabetic, NA
*BG↓, Fisetin treatment showed a significant decline in the levels of blood glucose, glycosylated hemoglobin (HbA1c), NF-kB p65 unit (in pancreas) and IL-1β (plasma), serum nitric oxide (NO) with an elevation in plasma insulin
*NF-kB↓,
*IL1β↓,
*NO↓,
*Insulin↑,
*SOD↑, Furthermore, the levels of activities of enzymatic antioxidants such as SOD, CAT, GPx, and GST were significantly improved in fisetin treated diabetic rats.
*Catalase↑,
*GPx↑,
*GSTs↑,

2861- FIS,    The neuroprotective effects of fisetin, a natural flavonoid in neurodegenerative diseases: Focus on the role of oxidative stress
- Review, Nor, NA - Review, Stroke, NA - Review, Park, NA
*antiOx↑, Fisetin is a flavonoid that exhibits potent antioxidant properties and protects the cells against OS
*ROS↓, The antioxidant properties of this flavonoid diminish oxidative stress, ROS production, neurotoxicity, neuro-inflammation, and neurological disorders.
*neuroP↑,
*NO↑, inhibits NO production.
BioAv↝, oral bioavailability of fisetin was reported 7.8 and 31.7% for oral doses of 100 and 200 mg/kg, respectively
*BBB↑, BBB permeability, fisetin can also affect hippocampal synaptic plasticity indirectly through the peripheral system
*toxicity↑, Furthermore, it did not show signs of toxicity at doses up to 2 g/kg in an acute toxicity study with no toxicity in the histopathological analysis of the heart, lungs, kidneys, liver, stomach, intestines, spleen and reproductive organs
*eff↑, potential benefits against neurological health complications and neurodegenerative diseases like AD, PD. HD, ALS, vascular dementia, schizophrenia, stroke, depression, diabetic neuropathy and traumatic brain injury
*GSH↑, direct antioxidant activity in addition to increasing intracellular antioxidants such as glutathione
*SOD↑, fig 2
*Aβ↓,
*12LOX↓,
*COX2/PTGS2↓,
*Catalase↑, Fisetin treatment prevented behavioral deficits, increased brain antioxidant, superoxide dismutase, catalase, reduced glutathione, and BDNF
*Inflam↓, decreased serum homocysteine, and pro-inflammatory biomarkers (TNF-α, IL-6), lipid peroxidation
*TNF-α↓,
*IL6↑,
*lipid-P↓,
NF-kB↓, suppressed the up-regulation of NF-κB, and IDO-1 genes expression, and decreased the rise of IL-1β levels.
IL1β↓,
NRF2↑, fisetin treatment also restored the downregulation of Nrf-2, HO-1, and ChAT genes expression and BDNF levels in the hippocampus, suggesting its protective effect against oxidative stress
HO-1↑,
GSTs↑, Fisetin also restored the AlCl3-induced reduction in the levels of SOD, CAT, GST, and GSH in a study that analysed the effect of this compound on AlCl3-induced reactive gliosis and neuronal inflammation in the brain of mice
cognitive↑, Fisetin improves neurodegenerative disease-associated dementia, cognitive functions and behavioral abnormalities along with increasing age
*BDNF↑, Fisetin also increases BDNF activity to prevent neurodegeneration

2860- FIS,    Fisetin induces autophagy in pancreatic cancer cells via endoplasmic reticulum stress- and mitochondrial stress-dependent pathways
- in-vitro, PC, PANC1 - in-vitro, PC, Bxpc-3 - in-vitro, Nor, hTERT-HPNE - in-vivo, NA, NA
AMPK↑, We found that the AMPK/mTOR signaling pathway was enhanced after fisetin treatment
mTOR↑,
UPR↑, RNA-seq analysis revealed that the unfolded protein response pathway, which is activated by ER stress, was enriched
ER Stress↑, Fisetin induced ER stress in pancreatic cancer cells
selectivity↑, results showed that fisetin was less cytotoxic to normal cells compared with pancreatic cancer cells
TumCP↓, fisetin inhibited the proliferation of PANC-1 cells
PERK↑, expression of PERK, ATF4, and ATF6 were also upregulated by fisetin
ATF4↑,
ATF6↑,

6915- FIS,  SRF,    Fisetin, a dietary flavonoid, augments the anti-invasive and anti-metastatic potential of sorafenib in melanoma
- in-vitro, Melanoma, NA
EMT↓, We have shown that fisetin, a flavonoid, reduces human melanoma cell invasion by inhibiting EMT.
TumCP↓, fisetin inhibited melanoma cell proliferation and tumor growth by downregulating the PI3K pathway.
PI3K↓,
eff↑, We found that combination treatment (fisetin + sorafenib) more effectively reduced the migration and invasion of BRAF-mutated melanoma cells both in vitro and in raft cultures compared to individual agents.
N-cadherin↓, Combination treatment also effectively inhibited EMT as observed by a decrease in N-cadherin, vimentin and fibronectin and an increase in E-cadherin both in vitro and in xenograft tumors.
Vim↓,
Fibronectin↓,
E-cadherin↑,
Snail↓, combination therapy effectively inhibited Snail1, Twist1, Slug and ZEB1 protein expression compared to monotherapy.
Twist↓,
Slug↓,
Zeb1↓,
MMP2↓, expression of MMP-2 and MMP-9 in xenograft tumors was further reduced in combination treatment compared to individual agents.
MMP9↓,
TumCI↓, Our findings demonstrate that fisetin potentiates the anti-invasive and anti-metastatic effects of sorafenib
TumMeta↓,
ChemoSen↑,

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↑,

6922- FIS,    Inhibition of Akt/mTOR signaling by the dietary flavonoid fisetin
- Review, Var, NA
*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

6921- FIS,    The Effects of Fisetin on Reducing Biological Aging: A Pilot Study
- Human, Nor, NA
*Dose↝, Fisetin 500 mg daily was administered for one week per month for six months.
*AntiAge⇅, four out of ten healthy adults experienced a reduction in biological aging, five out of ten saw an increase, and one out of ten had no change.

6920- FIS,    A phase II randomized placebo-controlled study of fisetin to improve physical function in breast cancer survivors: the TROFFi study rationale and trial design
- Trial, BC, NA
Dose↝, randomized 1:1 to receive either placebo or fisetin (20 mg/kg/day) on days 1–3 of a 14-day cycle for four cycles.
cellSen?, This is one of the first studies to test whether targeting senescence with an oral senolytic agent, fisetin, can mitigate physical function decline in postmenopausal breast cancer survivors treated with neo/adjuvant chemotherapy.

6919- FIS,    Inhibition of c-Jun N-terminal kinase and nuclear factor κ B pathways mediates fisetin-exerted anti-inflammatory activity in lipopolysccharide-treated RAW264.7 cells
TumCP↓, Although fisetin, a natural flavonoid, was known to inhibit proliferation, carcinogenesis and inflammation, the underlying anti-inflammatory mechanism of fistein still remains unclear.
Inflam↓,
NO↓, fisetin significantly reduced the nitrate oxide (NO) production and also inhibited the expression of pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) at protein and mRNA levels in LPS-stimulated c
iNOS↓,
COX2/PTGS2↓,
IL6↓, fisetin significantly reduced the LPS-stimulated secretion of proinflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor α (TNF-α).
TNF-α↓,
NF-kB↓, fisetin suppressed the activation of nuclear factor κ B (NF-κB) and the phosphorylation of c-Jun N-terminal kinase (JNK)
p‑cJun↓,

6918- FIS,  Geld,  Radic,    HSP90 Inhibitors, Geldanamycin and Radicicol, Enhance Fisetin-Induced Cytotoxicity via Induction of Apoptosis in Human Colonic Cancer Cells
- in-vitro, CRC, COLO205
eff↑, Compared to FIS treatment alone of COLO205 cells, GA and RAD significantly enhanced FIS-induced cytotoxicity, increased expression of cleaved caspase-3 and the PAPR protein, and produced a greater density of DNA ladder formation.
cl‑Casp3↑,
PARP↑,
MMPs↓, GA and RAD also reduced the MMPs with induction of caspase-9 protein cleavage in FIS-treated COLO205 cells.
cl‑Casp9↑,
other↝, The evidence supports HSP90 inhibitors possibly sensitizing human colon cancer cells to FIS-induced apoptosis, and treating colon cancer by combining HSP90 inhibitors with FIS deserves further in vivo study.

6917- FIS,    Dietary flavonoid fisetin regulates aluminium chloride-induced neuronal apoptosis in cortex and hippocampus of mice brain
- in-vivo, AD, NA - in-vivo, Park, NA
*neuroP↑, Given that fisetin exerts neuroprotection
*Dose↝, Fisetin (15 mg/Kg. b.wt. orally) was administered for 4 weeks before AlCl3-induction and administered simultaneously for 8 weeks during AlCl3-induction.
*Aβ↓, fisetin significantly (P<0.05) reduced Aβ aggregation, ASK-1, p-JNK, p53, cytochrome c, caspase-9 and 3 protein expressions and modulated Bax/Bcl-2 ratio.
*ASK1↓,
*p‑JNK↓,
*P53↓,
*Cyt‑c↓,
*Casp9↓,
*Bax:Bcl2↝,

6916- FIS,    Fisetin regulates TPA-induced breast cell invasion by suppressing matrix metalloproteinase-9 activation via the PKC/ROS/MAPK pathways
- in-vitro, BC, MCF7
PCK1↓, found to inhibit the activation of the PKCα/ROS/ERK1/2 and p38 MAPK signaling pathways.
ROS↓,
ERK↓,
MAPK↓,
p38↓,
NF-kB?, furthermore associated with reduced NF-κB activation, suggesting that the anti-invasive effect of fisetin on MCF-7 cells may result from inhibited TPA activation of NF-κB and reduced TPA activation of PKCα/ROS/ERK1/2 and p38 MAPK

1113- FIS,    Fisetin suppresses migration, invasion and stem-cell-like phenotype of human non-small cell lung carcinoma cells via attenuation of epithelial to mesenchymal transition
- in-vitro, Lung, A549 - in-vitro, Lung, H1299
TumCI↓,
TumCMig↓,
EMT↓,
E-cadherin↑, A549
ZO-1↑, h1299
Vim↓,
N-cadherin↓,
MMP2↓,
CD44↓,
CD133↓,
β-catenin/ZEB1↓,
NF-kB↓,
EGFR↓,
STAT3↓,
CSCs↓, ability of fisetin to serve as a potential therapeutic agent on its capacity to attenuate the EMT program and inhibit migration, invasion and stem cell phenotype of lung cancer cells.

6914- FIS,    Fisetin inhibits inflammation and induces autophagy by mediating PI3K/AKT/mTOR signaling in LPS-induced RAW264.7 cells
- in-vitro, Nor, RAW264.7
*p‑PI3K↓, fisetin reduced the elevated expression of p-PI3K, p-AKT and p-mTOR induced by LPS in a concentration-dependent manner.
*p‑Akt↓,
*p‑mTOR↓,

6913- FIS,    Fisetin inhibits tau aggregation by interacting with the protein and preventing the formation of β-strands
- in-vitro, AD, NA
*Aβ↓, In this study, we show that fisetin, a plant-derived polyphenol compound, can inhibit aggregation of the tau fragment, K18, and can disaggregate tau K18 filaments in vitro.

6912- FIS,    Cancer chemopreventive role of fisetin: Regulation of cell signaling pathways in different cancers
- Review, Var, NA
TumMeta↓, Fisetin has also been shown to inhibit the metastatic spread of cancer cells in tumor-bearing mice.
chemoPv↑, Fisetin has remarkable potential as chemopreventive agent and future studies must converge on the identification of additional regulatory roles of fisetin for inhibition and prevention of cancers.
VEGF↓, fisetin-mediated regulation of VEGF/VEGFR, EGFR, necroptosis and Hippo pathway.
VEGFR1↓,
EGFR↓,
Necroptosis↑,
Hippo↝,

6911- FIS,    New Mitochondria-Targeted Fisetin Derivative Compromises Mitophagy and Limits Survival of Drug-Induced Senescent Breast Cancer Cells
- vitro+vivo, BC, NA
MMP↓, Mito-fisetin, when used at low micromolar concentrations, stimulated the dissipation of mitochondrial membrane potential and oxidative stress, and affected mitochondrial function, resulting in apoptosis induction in senescent breast cancer cells.
mt-ROS↑, Mito-Fisetin mF3 Induces Oxidative Stress in Mitochondria
Apoptosis↑,
p‑AMPK↑, Mito-fisetin-mediated cytotoxicity was due to increased levels of phosphorylated AMPK, decreased levels of AKT and HSP90,
Akt↓,
HSP90↓,
PI3K↓, Fisetin may interfere with the activity of cell survival promoting signaling pathways such as PI3K/AKT/mTOR and mitochondrial function to stimulate anticancer effects by the inhibition of cell proliferation, metastatic potential, and angiogenesis and
Akt↓,
mTOR↓,
TumCP↓,
TumMeta↓,
angioG↓,
TumCD↑,
selectivity↑, Normal cells were less sensitive to mito-fisetin treatment
TumVol↓, Mito-Fisetin mF3 Inhibits Tumor Size and Induces Cytotoxicity In Vivo

6910- FIS,    Exploring the therapeutic promise of fisetin: molecular mechanisms and clinical aspects in lung cancer
- in-vitro, Lung, NA
Apoptosis↑, roles include the promotion of apoptosis, inhibition of cell proliferation, migration, and invasion, as well as the regulation of autophagy.
TumCP↓,
TumCMig↓,
TumCI↓,
TumAuto↝,
ChemoSen↑, fisetin improves the effectiveness of conventional treatments as a chemo- and radiosensitizer and minimizes side effects.
RadioS↑,
chemoP↑,
BioAv↓, overall utility of fisetin for clinical use is now somewhat restricted by its poor solubility and short half-life.
Half-Life↓,

6909- FIS,    Modulation of PI3K/ AKT/ mTOR and apoptosis pathway in colon cancer cells by the plant flavonoid fisetin
- in-vitro, Colon, Caco-2
AntiCan↑, Fisetin, a plant-derived flavonoid, has shown promising effects as an anticancer agent against several human cancers, including colon cancer.
tumCV↓, Fisetin markedly decreased the cell viability in a dose- and time-dependent manner.
Bcl-2↓, Fisetin down-regulated BCL-2, PI3K, mTOR, and NF-κB gene expression while up-regulating BAX gene expression.
PI3K↓,
mTOR↓,
NF-kB↓,
BAX↑,
*AntiDiabetic↑, Fisetin has gained extensive attention for its remarkable biological activities, such as anticancer, antidiabetic, anti-inflammatory, antioxidant, and neuroprotective effects (
*AntiCan↑,
*Inflam↓,
*antiOx↑,
*neuroP↑,

6908- FIS,    Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer's disease transgenic mice
- in-vivo, AD, NA
*memory↑, We show here that oral administration of fisetin to APPswe/PS1dE9 double transgenic AD mice from 3 to 12 months of age prevents the development of learning and memory deficits.
*p‑ERK↑, This correlates with an increase in ERK phosphorylation along with a decrease in protein carbonylation, a marker of oxidative stress.
*CDK5↓, fisetin also reduces the levels of the cyclin-dependent kinase 5 (Cdk5) activator p35 cleavage product, p25, in both control and AD brains.
*P21↓,
*cognitive↑, Given the clear improvement in both cognitive and neuropsychiatric behavior in the AD mice fed fisetin
*ROS↓, Previously, it was shown that fisetin is able to reduce markers of oxidative stress in cell culture neuroprotection assays
*COX2/PTGS2↓, cyclooxygenase 2 (Cox2) and 12-lipoxygenase (12-LOX) was reduced by treatment with fisetin
*12LOX↓,
PGD2↓, fisetin increased production of prostaglandin D2 (PGD2)

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

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

2841- FIS,    Fisetin, an Anti-Inflammatory Agent, Overcomes Radioresistance by Activating the PERK-ATF4-CHOP Axis in Liver Cancer
- in-vitro, Nor, RAW264.7 - in-vitro, Liver, HepG2 - in-vitro, Liver, Hep3B - in-vitro, Liver, HUH7
*Inflam↓, fisetin reduced the LPS-induced production of pro-inflammation markers, such as TNF-α, IL-1β, and IL-6, demonstrating the anti-inflammatory effects of fisetin
*TNF-α↓,
*IL1β↓,
*IL6↓,
Apoptosis↓, fisetin induced apoptotic cell death and ER stress through intracellular calcium (Ca2+) release, the PERK-ATF4-CHOP signaling pathway, and induction of GRP78 exosomes.
ER Stress↑,
Ca+2↑,
PERK↑, inducing the GRP78-PERK-ATF4-CHOP pathway in fisetin-treated radioresistant liver cancer cells.
ATF4↑, fisetin treatment of HepG2 and Hep3B cells resulted in the upregulation of ATF4 and CHOP in a time-dependent manner
CHOP/DDIT3↑,
GRP78/BiP↑,
tumCV↓, fisetin decreased the cell viability and increased LDH activity in HepG2, Hep3B, and Huh7 cells in a concentration-dependent manner
LDH↑,
Casp3↑, caspase-3 activity was significantly enhanced
cl‑Casp3↑, fisetin treatment significantly increased the pro-apoptotic markers, including cleaved caspase-3, caspase-8, and caspase-9
cl‑Casp8↑,
cl‑Casp9↑,
p‑eIF2α↑, fisetin treatment increased CHOP, p-eIF2α, ATF4, p-PERK, and GRP78 levels
RadioS↑, Radiation Combined with Fisetin Overcomes Radioresistance

2840- FIS,    Fisetin-induced cell death, apoptosis, and antimigratory effects in cholangiocarcinoma cells
- NA, CCA, NA
ROS↑, The mechanism of cell death and apoptosis was measured by reactive oxygen species (ROS) generation
TumCMig↓, Fisetin may inhibit cholangiocarcinoma (CCA) cell migration and proliferation;
TumCP↓,

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

2838- FIS,    Fisetin induces apoptosis in colorectal cancer cells by suppressing autophagy and down-regulating nuclear factor erythroid 2-related factor 2 (Nrf2)
cl‑Casp3↑, enhanced signals for the cleaved caspase 3 and nuclear PARP-1 in those fisetin-treated cells
cl‑PARP↑,
MMP↓, This was consistent with the collapse of mitochondrial membrane potential and release of cytochrome c
Cyt‑c↑,
ROS↑, fisetin-treated cells showed increased ROS level
NRF2↓, and a significant decline in nuclear Nrf2 immunosignal versus recovery in nuclear Nrf2 due to the treatment with curcumin and resveratrol (Nrf2 activators) and thus, suggesting a role of Nrf2 suppression in fisetin-mediated apoptosis in SW-480 cells.

2833- FIS,  AgNPs,    Glucose-capped fisetin silver nanoparticles induced cytotoxicity and ferroptosis in breast cancer cells: A molecular perspective
- in-vitro, BC, MDA-MB-231
MMP↓, MDA-MB-231 cells treated with glucose-capped fisetin silver nanoparticles showed signs of apoptosis, decreased mitochondrial membrane potential, and elevated Reactive oxygen species (ROS) production.
ROS↑,
NRF2↑, upregulation of SLC7A11, SLC40A1, NRF2F, NOX2, and NOX5 genes that are associated with various crucial cellular events
NOX↑,
selectivity↑, Glucose nanoparticles selectively deliver cytotoxic agents to cancer cells by targeting the glucose transporters overexpressed in cancer cells, resulting in minimal toxicity to healthy tissues

2832- FIS,    Fisetin's Promising Antitumor Effects: Uncovering Mechanisms and Targeting for Future Therapies
- Review, Var, NA
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↓,

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.

2858- FIS,    Fisetin inhibits cell migration via inducing HO-1 and reducing MMPs expression in breast cancer cell lines
- in-vitro, BC, 4T1
HO-1↑, fisetin increased HO-1 mRNA and protein expressions
NRF2↑, fisetin also elevated Nrf2 expression in nuclear fraction
MMP2↓, fisetin decreased MMP-2 and MMP-9 enzyme activity and gene expression in both protein and mRNA levels.
MMP9↓,

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,

2828- FIS,    Fisetin, a Potent Anticancer Flavonol Exhibiting Cytotoxic Activity against Neoplastic Malignant Cells and Cancerous Conditions: A Scoping, Comprehensive Review
- Review, Var, NA
*neuroP↑, As a hydrophobic agent, FIS readily penetrates cell membranes and accumulates in cells to exert neuroprotective, neurotrophic and antioxidant effects
*antiOx↑,
*Inflam↓, FIS treatment may include alleviating inflammation, cell apoptosis and oxidative stress
RenoP↑, alleviates cell apoptosis and inflammation in acute kidney injury
COX2/PTGS2↓, FIS induces apoptosis in various tumor cells by, for example, inhibiting cyclooxygenase-2, inhibiting the Wnt/EGFR/NF-κB pathway, activating the caspase-3 cascade
Wnt↓,
EGFR↓,
NF-kB↓,
Casp3↑,
Ca+2↑, activating the caspase-3 and Ca2+ dependent endonuclease, and activating the caspase-8/caspase-3 dependent pathway via ERK1/2.
Casp8↑,
TumCCA↑, FIS controls the cell cycle and inhibits cyclin-dependent kinases (CDKs) in human cancer cell lines,
CDK1↓,
PI3K↓, by inhibition of PI3K/Akt/mTOR signaling [20], mitogen-activated protein kinases (MAPK) [21], and nuclear transcription factor (NF-κB)
Akt↓,
mTOR↓,
MAPK↓,
*P53↓, FIS inhibits aging by reducing p53, p21 and p16 expression in mouse and human tissues
*P21↓,
*p16↓,
mTORC1↓, FIS induces autophagic cell death by inhibiting both the mTORC1 and mTORC2 pathways
mTORC2↓,
P53↑, FIS significantly increases the expression of p53 and p21 proteins and lowers the levels of cyclin D1 [27,28], cyclin A, CDK4 and CDK2, thus contributing to cell-cycle arrest.
P21↑,
cycD1/CCND1↓,
cycA1/CCNA1↓,
CDK2↓,
CDK4↓,
BAX↑, FIS also increases Bax [27,28] and Bak [27] protein expression, but reduces the levels of Bcl-2 [27,28], Bcl-xL [27] and PCNA [28], and then starts the mitochondrial apoptotic pathway.
Bcl-2↓,
PCNA↓,
HER2/EBBR2↓, FIS reduces HER2 tyrosine phosphorylation in a dose-dependent manner and aids in proteasomal degradation of HER2 rather than lysosomal degradation
Cyt‑c↑, FIS cells causes destabilization of the mitochondrial membrane and an increase in cytochrome c levels, which is consistent with the loss of mitochondrial membrane integrity.
MMP↓,
cl‑Casp9↑,
MMP2↓, FIS reduces the enzymatic activity of both MMP-2 and MMP-9.
MMP9↓,
cl‑PARP↑, cell membrane, mitochondrial depolarization, activation of caspase-7, -8 and -9, and cleavage of PARP
uPA↓, interestingly, the promoter activity of the uPA gene is suppressed by FIS
DR4↑, induces upregulation of DR4 and DR5 death receptor expression in a dose-dependent manner
DR5↑,
ROS↓, FIS induces an increase in intracellular Ca2+ but reduces the production of ROS in WEHI-3 cells (myelomonocytic leukemia)
AIF↑, It also increases the levels of caspase-3 and AIF mRNA, but also increases necrosis markers including RIP3 and PARP1
CDC25↓, FIS reduces the expression of cdc25a, but increases the expression of p-p53, Chk1, p21 and p27, which may lead to a G0/G1 arrest.
Dose↑, FIS in concentrations from 0 to 10 μM does not affect cell viability; however, its use at concentrations of 20–40 μM significantly reduces the viability of lung cancer cells
CHOP/DDIT3↑, CaKi : FIS induces upregulation of CHOP expression and ROS production
ROS↑, NCI-H460 :FIS increases the ER stress signaling FIS increases the level of mitochondrial ROS FIS induces mitochondrial Ca2+ overloading and ER stress FIS induced ER stress-mediated cell death via activation of the MAPK pathway
cMyc↓, FIS influences proliferation related genes such as cyclin D1, c-myc and cyclooxygenase (COX)-2 by downregulating them.
cardioP↑, cardioprotective activity

2827- FIS,    The Potential Role of Fisetin, a Flavonoid in Cancer Prevention and Treatment
- Review, Var, NA
*antiOx↑, effective antioxidant, anti-inflammatory
*Inflam↓,
neuroP↑, neuro-protective, anti-diabetic, hepato-protective and reno-protective potential.
hepatoP↑,
RenoP↑,
cycD1/CCND1↓, Figure 3
TumCCA↑,
MMPs↓,
VEGF↓,
MAPK↓,
NF-kB↓,
angioG↓,
Beclin-1↑,
LC3s↑,
ATG5↑,
Bcl-2↓,
BAX↑,
Casp↑,
TNF-α↓,
Half-Life↓, Fisetin was given at an effective dosage of 223 mg/kilogram intraperitoneally in mice. The plasma concentration declined biophysically, with a rapid half-life of 0.09 h and a terminal half-life of 3.1 h,
MMP↓, Fisetin powerfully improved apoptotic cells and caused the depolarization of the mitochondrial membrane.
mt-ROS↑, Fisetin played a role in the induction of apoptosis, independently of p53, and increased mitochondrial ROS generation.
cl‑PARP↑, fisetin-induced sub-G1 population as well as PARP cleavage.
CDK2↓, Moreover, the activities of cyclin-dependent kinases (CDK) 2 as well as CDK4 were decreased by fisetin and also inhibited CDK4 activity in a cell-free system, demonstrating that it might directly inhibit the activity of CDK4
CDK4↓,
Cyt‑c↑, Moreover, release of cytochrome c and Smac/Diablo was induced by fisetin
Diablo↑,
DR5↑, Fisetin caused an increase in the protein levels of cleaved caspase-8, DR5, Fas ligand, and TNF-related apoptosis-inducing ligand
Fas↑,
PCNA↓, Fisetin decreased proliferation-related proteins such as PCNA, Ki67 and phosphorylated histone H3 (p-H3) and decreased the expression of cell growth
Ki-67↓,
p‑H3↓,
chemoP↑, Paclitaxel treatment only showed more toxicity to normal cells than the combination of flavonoids with paclitaxel, suggesting that fisetin might bring some safety against paclitaxel-facilitated cytotoxicity.
Ca+2↑, Fisetin encouraged apoptotic cell death via increased ROS and Ca2+, while it increased caspase-8, -9 and -3 activities and reduced the mitochondrial membrane potential in HSC3 cells.
Dose↝, After fisetin treatment at 40 µM, invasion was reduced by 87.2% and 92.4%, whereas after fisetin treatment at 20 µM, invasion was decreased by 52.4% and 59.4% in SiHa and CaSki cells, respectively
CDC25↓, This study proposes that fisetin caused the arrest of the G2/M cell cycle via deactivating Cdc25c as well Cdc2 via the activation of Chk1, 2 and ATM
CDC2↓,
CHK1↑,
Chk2↑,
ATM↑,
PCK1↓, fisetin decreases the levels of SOS-1, pEGFR, GRB2, PKC, Ras, p-p-38, p-ERK1/2, p-JNK, VEGF, FAK, PI3K, RhoA, p-AKT, uPA, NF-ĸB, MMP-7,-9 and -13, whereas it increases GSK3β as well as E-cadherin in U-2 OS
RAS↓,
p‑p38↓,
Rho↓,
uPA↓,
MMP7↓,
MMP13↓,
GSK‐3β↑,
E-cadherin↑,
survivin↓, whereas those of survivin and BCL-2 were reduced in T98G cells
VEGFR2/KDR/Flk1↓, Fisetin inhibited the VEGFR expression in Y79 cells as well as the angiogenesis of a tumor.
IAP2/BIRC3↓, The downregulation of cIAP-2 by fisetin
STAT3↓, fisetin induced apoptosis in TPC-1 cells via the initiation of oxidative damage and enhanced caspases expression by downregulating STAT3 and JAK 1 signaling
JAK1↓,
mTORC1↓, Fisetin acts as a dual inhibitor of mTORC1/2 signaling,
mTORC2↓,
NRF2↑, Moreover, In JC cells, the Nrf2 expression was gradually increased by fisetin from 8 h to 24 h

2826- FIS,    Fisetin induces apoptosis in breast cancer MDA-MB-453 cells through degradation of HER2/neu and via the PI3K/Akt pathway
- in-vitro, BC, MDA-MB-453
Apoptosis↑, fisetin induced apoptosis of these cells by various mechanisms, such as inactivation of the receptor, induction of proteasomal degradation, decreasing its half-life, decreasing enolase phosphorylation, and alteration of PI3K/AKT
p‑ENO1↓,
DNAdam↑, displaying DNA fragmentation pattern
PI3K↑, Fisetin increased PI3K activity at 10 uM, which gradually declines on treatment with higher concentrations (25 or 50 uM)
p‑Akt↑, Fisetin (10 uM) increased phosphorylation of Akt in MDA-MB-453 cells greater than control. Higher concentrations of fisetin (25 or 50 uM) gradually decreased the phosphorylation of Akt.
HER2/EBBR2↓, fisetin induced HER2 depletion

2825- FIS,    Exploring the molecular targets of dietary flavonoid fisetin in cancer
- Review, Var, NA
*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.

2824- FIS,    Fisetin in Cancer: Attributes, Developmental Aspects, and Nanotherapeutics
- Review, Var, NA
*antiOx↑, Fisetin is one such naturally derived flavone that offers numerous pharmacological benefits, i.e., antioxidant, anti-inflammatory, antiangiogenic, and anticancer properties.
*Inflam↓,
angioG↓,
BioAv↓, poor bioavailability associated with its extreme hydrophobicity hampers its clinical utility
BioAv↑, The issues related to fisetin delivery can be addressed by adapting to the developmental aspects of nanomedicines, such as formulating it into lipid or polymer-based systems, including nanocochleates and liposomes
TumCP↓, fisetin also inhibits tumor proliferation by repressing tumor mass multiplication, invasion, migration, and autophagy.
TumCI↓,
TumCMig↓,
*neuroP↑, figure 2
EMT↓, It affects the cell cycle and thereby cell proliferation, microtubule assembly, cell migration and invasion, epithelial to mesenchymal transition (EMT), and cell death
ROS↑, cell death caused by fisetin is possibly due to the induction of apoptosis by fisetin or other signaling molecules and reactive oxygen species (ROS)
selectivity↑, Without influencing the growth of normal cells, fisetin has the capability to hinder the formation of colonies and inhibit the multiplication of cancer cells.
EGFR↓, fisetin restricts the multiplication of EGFR 2-overexpressing SK-BR-3 breast tumor masses
NF-kB↓, fisetin inhibits cancer metastasis by reducing the expressions of nuclear factor-kB (NF-kB)-modulated metastatic proteins in a variety of tumor cell types, including vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP)
VEGF↓,
MMP9↓,
MMP↓, rupturing the plasma membrane, depolarizing mitochondria, cleaving PARP, and activating caspase-7, -8, and -9.
cl‑PARP↑,
Casp7↑,
Casp8↑,
Casp9↑,
*ROS↓, Fisetin is a bioactive flavonol molecule that can easily penetrate the cell membrane due to its hydrophobic nature [51,52], reducing the generation of inflammatory cytokines and reactive oxygen species (ROS) in microglial cells, (normal cells)
uPA↓, Perhaps fisetin lowers angiogenesis, consequently suppressing tumor multiplication by urokinase plasminogen activator (uPA) inhibition
MMP1↓, powerful matrix metalloproteinase (MMP)-1 inhibitor
Wnt↓, Fisetin works on several cellular pathways, such as Wnt, Akt-PI3K, and ERK, as an inhibitor
Akt↓,
PI3K↓,
ERK↓,
Half-Life↝, Fisetin exhibits a very short terminal half-life of approximately 3 hrs in its free form. This half-life is found to be less than that of its metabolites


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↑, 1,   GSTs↑, 1,   HO-1↑, 4,   lipid-P↓, 1,   NRF2↓, 1,   NRF2↑, 6,   ROS↓, 8,   ROS↑, 10,   mt-ROS↑, 3,  

Mitochondria & Bioenergetics(tgid=3) ⓘ

AIF↑, 2,   CDC2↓, 2,   CDC25↓, 4,   EGF↓, 1,   MMP↓, 10,   mtDam↑, 1,   XIAP↓, 3,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

AMPK↑, 5,   p‑AMPK↑, 1,   cMyc↓, 1,   p‑ENO1↓, 1,   LDH↑, 1,   PCK1↓, 2,  

Cell Death(tgid=5) ⓘ

Akt↓, 13,   p‑Akt↓, 1,   p‑Akt↑, 1,   Apoptosis↓, 1,   Apoptosis↑, 10,   Bak↑, 2,   BAX↑, 5,   Bcl-2↓, 7,   Bcl-xL↓, 2,   BID↑, 1,   BIM↑, 1,   Casp↑, 3,   Casp3↑, 6,   cl‑Casp3↑, 5,   Casp7↑, 1,   Casp8↑, 5,   cl‑Casp8↑, 1,   Casp9↑, 6,   cl‑Casp9↑, 4,   Chk2↑, 1,   Cyt‑c↑, 8,   Diablo↑, 3,   DR4↑, 1,   DR5↑, 3,   Fas↑, 1,   Hippo↝, 1,   IAP1↓, 1,   IAP2/BIRC3↓, 3,   iNOS↓, 1,   JNK↑, 3,   MAPK↓, 5,   MAPK↑, 1,   Mcl-1↓, 2,   Necroptosis↑, 1,   p27/CDKN1B↓, 1,   p27/CDKN1B↑, 3,   p38↓, 2,   p38↑, 1,   p‑p38↓, 1,   survivin↓, 4,   TRAILR↑, 1,   TumCD↑, 2,  

Kinase & Signal Transduction(tgid=6) ⓘ

HER2/EBBR2↓, 3,   p70S6↓, 1,   TSC2↑, 1,  

Transcription & Epigenetics(tgid=7) ⓘ

cJun↓, 4,   p‑cJun↓, 1,   p‑H3↓, 1,   other↝, 2,   tumCV↓, 4,  

Protein Folding & ER Stress(tgid=8) ⓘ

ATF6↑, 1,   CHOP/DDIT3↑, 3,   p‑eIF2α↑, 1,   ER Stress↑, 7,   GRP78/BiP↑, 4,   HSF1↓, 1,   HSP27↓, 1,   HSP70/HSPA5↓, 1,   HSP90↓, 1,   IRE1↑, 3,   PERK↑, 2,   UPR↑, 1,  

Autophagy & Lysosomes(tgid=9) ⓘ

ATG5↑, 1,   Beclin-1↑, 1,   LC3II↑, 1,   LC3s↑, 1,   TumAuto↑, 2,   TumAuto↝, 1,  

DNA Damage & Repair(tgid=10) ⓘ

ATM↑, 1,   CHK1↑, 1,   DNAdam↑, 8,   P53↑, 8,   PARP↑, 1,   cl‑PARP↑, 10,   PCNA↓, 2,   γH2AX↑, 2,  

Cell Cycle & Senescence(tgid=11) ⓘ

CDK1↓, 2,   CDK2↓, 10,   CDK2↑, 1,   CDK4↓, 9,   CDK4↑, 1,   cycA1/CCNA1↓, 2,   CycB/CCNB1↓, 1,   cycD1/CCND1↓, 10,   cycE/CCNE↓, 6,   P21↓, 1,   P21↑, 7,   Securin↓, 1,   TumCCA↑, 13,  

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

4E-BP1↑, 1,   CD133↓, 2,   CD44↓, 2,   cFos↓, 4,   CSCs↓, 2,   EMT↓, 8,   ERK↓, 7,   GSK‐3β↑, 1,   mTOR↓, 11,   mTOR↑, 1,   mTORC1↓, 5,   mTORC2↓, 4,   PI3K↓, 14,   PI3K↑, 1,   PTEN↑, 3,   RAS↓, 1,   STAT3↓, 3,   TCF↓, 1,   TCF-4↓, 2,   TOP1↓, 1,   TOP2↓, 1,   TumCG↓, 9,   Wnt↓, 6,  

Migration(tgid=13) ⓘ

AP-1↓, 2,   Ca+2↑, 4,   E-cadherin↑, 5,   FAK↓, 1,   Fibronectin↓, 1,   Ki-67↓, 2,   MMP1↓, 2,   MMP13↓, 1,   MMP2↓, 9,   MMP7↓, 4,   MMP9↓, 9,   MMPs↓, 3,   N-cadherin↓, 3,   PKCδ↓, 2,   Rho↓, 1,   Slug↓, 1,   Snail↓, 1,   TET1↓, 1,   TGF-β↓, 1,   TumCA↓, 1,   TumCI↓, 9,   TumCMig↓, 9,   TumCP↓, 12,   TumMeta↓, 4,   Twist↓, 2,   uPA↓, 11,   VEGFR1↓, 1,   Vim↓, 4,   Zeb1↓, 1,   ZO-1↑, 1,   β-catenin/ZEB1↓, 5,  

Angiogenesis & Vasculature(tgid=14) ⓘ

angioG↓, 6,   ATF4↑, 5,   EGFR↓, 8,   NO↓, 1,   NO↑, 1,   VEGF↓, 5,   VEGFR2/KDR/Flk1↓, 1,  

Barriers & Transport(tgid=15) ⓘ

P-gp/ABCB1↓, 1,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

cellSen?, 1,   COX2/PTGS2↓, 7,   IL1β↓, 1,   IL6↓, 1,   Inflam↓, 3,   JAK1↓, 1,   NF-kB?, 1,   NF-kB↓, 15,   PGD2↓, 1,   PGE2↓, 4,   PSA↓, 2,   TNF-α↓, 2,  

Cellular Microenvironment(tgid=17) ⓘ

NOX↑, 1,  

Hormonal & Nuclear Receptors(tgid=20) ⓘ

AR↓, 1,   CDK6↓, 2,   CDK6↑, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

BioAv↓, 3,   BioAv↑, 3,   BioAv↝, 1,   ChemoSen↑, 6,   Dose↑, 1,   Dose↝, 4,   eff↓, 1,   eff↑, 8,   Half-Life↓, 2,   Half-Life↝, 2,   RadioS↑, 8,   selectivity↑, 7,  

Clinical Biomarkers(tgid=22) ⓘ

AR↓, 1,   EGFR↓, 8,   HER2/EBBR2↓, 3,   IL6↓, 1,   Ki-67↓, 2,   LDH↑, 1,   PSA↓, 2,  

Functional Outcomes(tgid=23) ⓘ

AntiCan↑, 1,   cardioP↑, 1,   chemoP↑, 2,   chemoPv↑, 1,   cognitive↑, 1,   hepatoP↑, 1,   neuroP↑, 1,   RenoP↑, 2,   TumVol↓, 2,  
Total Targets: 218

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

antiOx↓, 1,   antiOx↑, 8,   Catalase↑, 3,   GPx↑, 1,   GSH↑, 5,   GSTs↑, 1,   HO-1↑, 3,   lipid-P↓, 2,   NRF2↑, 4,   ROS↓, 6,   SOD↑, 3,  

Mitochondria & Bioenergetics(tgid=3) ⓘ

Insulin↑, 1,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

12LOX↓, 2,   p‑cMyc↑, 1,   p‑CREB↑, 1,  

Cell Death(tgid=5) ⓘ

p‑Akt↓, 1,   ASK1↓, 1,   Bax:Bcl2↝, 1,   Casp9↓, 1,   Cyt‑c↓, 1,   JNK↓, 1,   p‑JNK↓, 1,  

Autophagy & Lysosomes(tgid=9) ⓘ

TFEB↑, 1,  

DNA Damage & Repair(tgid=10) ⓘ

p16↓, 1,   P53↓, 2,  

Cell Cycle & Senescence(tgid=11) ⓘ

P21↓, 2,  

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

ERK↑, 2,   p‑ERK↑, 1,   mTOR↓, 1,   p‑mTOR↓, 1,   mTORC1↓, 1,   p‑PI3K↓, 1,  

Migration(tgid=13) ⓘ

5LO↓, 2,   CDK5↓, 1,   MMP9↓, 1,  

Angiogenesis & Vasculature(tgid=14) ⓘ

NO↓, 1,   NO↑, 1,  

Barriers & Transport(tgid=15) ⓘ

BBB↑, 1,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

cellSen↑, 1,   COX2/PTGS2↓, 2,   IL1β↓, 2,   IL6↓, 1,   IL6↑, 1,   Inflam↓, 12,   NF-kB↓, 3,   TNF-α↓, 3,  

Synaptic & Neurotransmission(tgid=18) ⓘ

BDNF↑, 1,   p‑tau↓, 1,  

Protein Aggregation(tgid=19) ⓘ

Aβ↓, 3,  

Drug Metabolism & Resistance(tgid=21) ⓘ

BioAv↓, 1,   BioAv↑, 1,   Dose↝, 2,   eff↑, 2,   Half-Life↓, 1,   selectivity⇅, 1,  

Clinical Biomarkers(tgid=22) ⓘ

BG↓, 1,   IL6↓, 1,   IL6↑, 1,  

Functional Outcomes(tgid=23) ⓘ

AntiAge↑, 2,   AntiAge⇅, 1,   AntiCan↑, 1,   AntiDiabetic↑, 2,   cardioP↑, 1,   chemoPv↑, 2,   cognitive↑, 1,   memory↑, 5,   neuroP↑, 8,   toxicity↑, 1,  
Total Targets: 68

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#:%  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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