Fisetin / angioG 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
angioG, angiogenesis: Click to Expand ⟱
Source:
Type:
Process through which new blood vessels.
Angiogenesis, the process of new blood vessel formation from pre-existing vessels, plays a crucial role in cancer progression and metastasis. Tumors require a blood supply to grow beyond a certain size and to spread to other parts of the body.
Vascular Endothelial Growth Factor (VEGF): VEGF is one of the most important pro-angiogenic factors. It stimulates endothelial cell proliferation and migration, leading to the formation of new blood vessels. Many tumors overexpress VEGF, which correlates with poor prognosis.
Hypoxia-Inducible Factor (HIF): In response to low oxygen levels (hypoxia), tumors can activate HIF, which in turn promotes the expression of VEGF and other angiogenic factors. This mechanism allows tumors to adapt to their microenvironment and sustain growth.
-Tumour development and progression beyond a size of few millimetres‐cubed crucially depends on the onset of angiogenesis, that is, the ‘angiogenic switch’
Scientific Papers found: Click to Expand⟱
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.

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↓,

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

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

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/ATG6↑,
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

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

2847- FIS,    Fisetin-induced cell death, apoptosis, and antimigratory effects in cholangiocarcinoma cells
- in-vitro, CCA, NA
tumCV↓, Fisetin was significant in suppressing CCA cell viability and colony formation during the course of this experiment.
ChemoSen↑, fisetin significantly potentiated the cisplatin-induced CCA cells death
TumCMig↓, reduced the migration of cancer cells and demonstrated more pronounced effects on KKU-M452 cells
ROS↑, fisetin prompted cell death and apoptosis in CCA cells by stimulating the generation of ROS in KKU-100 cells at a dosage of 50 μM
TumCI↓, suppression of cell invasion and migration,prevention of angiogenesis
angioG↓,
CDK2↓, mechanisms including the suppression of cyclin-dependent kinases, the inhibition of PI3K/Akt/mTOR
PI3K↓,
Akt↓,
mTOR↓,
EGFR↓, suppression of the EGFR pathway, the stimulation of the caspase cascade
Casp↑,
mTORC1↓, suppressing the mTORC1 and 2 signaling
mTORC2↑,
cycD1/CCND1↓, decreasing the level of the cyclin D1 and cyclin E mRNA
cycE/CCNE↓,
MMP2↓, Matrix metalloproteinases (MMP) 2 and MMP 9 gene expression and enzyme activity are suppressed
MMP9↓,
ER Stress↑, Moreover, fisetin also caused endoplasmic reticulum (ER) stress-induced production of mitochondrial ROS generation and Ca2+, with the involvement of MAPK signaling
Ca+2↑,
eff↓, The ROS scavenger molecule N-acetyl cysteine decreased fisetin-activated apoptosis in multiple myeloma and oral cancer cells

2845- FIS,    Fisetin: A bioactive phytochemical with potential for cancer prevention and pharmacotherapy
- Review, Var, NA
PI3K↓, block multiple signaling pathways such as the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) and p38
Akt↓,
mTOR↓,
p38↓,
*antiOx↑, antioxidant, anti-inflammatory, antiangiogenic, hypolipidemic, neuroprotective, and antitumor effect
*neuroP↑,
Casp3↑, U266 cancer cell line through activation of caspase-3, downregulation of Bcl-2 and Mcl-1L, upregulation of Bax, Bim and Bad
Bcl-2↓,
Mcl-1↓,
BAX↑,
BIM↑,
BAD↑,
AMPK↑, activation of 5'adenosine monophosphate-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC) and decreased phosphorylation of AKT and mTOR were also observed
ACC↑,
DNAdam↑, DNA fragmentation, mitochondrial membrane depolarizatio
MMP↓,
eff↑, fisetin in combination with a citrus flavanone, hesperetin mediated apoptosis by mitochondrial membrane depolarization and caspase-3 act
ROS↑, NCI-H460 human non-small cell lung cancer line, fisetin generated reactive oxygen species (ROS), endoplasmic reticulum (ER) stress
cl‑PARP↑, fisetin treatment resulted in PARP cleavage
Cyt‑c↑, release of cyt. c
Diablo↑, release of cyt. c and Smac/DIABLO from mitochondria,
P53↑, increased p53 protein levels
p65↓, reduced phospho-p65 and Myc oncogene expression
Myc↓,
HSP70/HSPA5↓, fisetin causes inhibition of proliferation by the modulation of heat shock protein 70 (HSP70), HSP27
HSP27↓,
COX2/PTGS2↓, anti-proliferative effects of fisetin through the activation of apoptosis via inhibition of cyclooxygenase-2 (COX-2) and Wnt/EGFR/NF-κB signaling pathways
Wnt↓,
EGFR↓,
NF-kB↓,
TumCCA↑, The anti-proliferative effects of fisetin and hesperetin were shown to be occurred through S, G2/M, and G0/G1 phase arrest in K562 cell progression
CDK2↓, decrease in levels of cyclin D1, cyclin A, Cdk-4 and Cdk-2
CDK4↓,
cycD1/CCND1↓,
cycA1/CCNA1↓,
P21↑, increase in p21 CIP1/WAF1 levels in HT-29 human colon cancer cell
MMP2↓, fisetin has exhibited tumor inhibitory effects by blocking matrix metalloproteinase-2 (MMP- 2) and MMP-9 at mRNA and protein levels,
MMP9↓,
TumMeta↓, Antimetastasis
MMP1↓, fisetin also inhibited the MMP-14, MMP-1, MMP-3, MMP-7, and MMP-9
MMP3↓,
MMP7↓,
MET↓, promotion of mesenchymal to epithelial transition associated with a decrease in mesenchymal markers i.e. N-cadherin, vimentin, snail and fibronectin and an increase in epithelial markers i.e. E-cadherin
N-cadherin↓,
Vim↓,
Snail↓,
Fibronectin↓,
E-cadherin↑,
uPA↓, fisetin suppressed the expression and activity of urokinase plasminogen activator (uPA)
ChemoSen↑, combination treatment of fisetin and sorafenib reduced the migration and invasion of BRAF-mutated melanoma cells both in in-vitro
EMT↓, inhibited epithelial to mesenchymal transition (EMT) as observed by a decrease in N-cadherin, vimentin and fibronectin and an increase in E-cadherin
Twist↓, inhibited expression of Snail1, Twist1, Slug, ZEB1 and MMP-2 and MMP-9
Zeb1↓,
cFos↓, significant decrease in NF-κB, c-Fos, and c-Jun levels
cJun↓,
EGF↓, Fisetin inhibited epidermal growth factor (EGF)
angioG↓, Antiangiogenesis
VEGF↓, decreased expression of endothelial nitric oxide synthase (eNOS) and VEGF, EGFR, COX-2
eNOS↓,
*NRF2↑, significantly increased nuclear translocation of Nrf2 and antioxidant response element (ARE) luciferase activity, leading to upregulation of HO-1 expression
HO-1↑,
NRF2↓, Fisetin also triggered the suppression of Nrf2
GSTs↓, declined placental type glutathione S-transferase (GST-p) level in the liver of the fisetin- treated rats with hepatocellular carcinoma (HCC)
ATF4↓, Fisetin also rapidly increased the levels of both Nrf2 and ATF4

2843- FIS,    Fisetin and Quercetin: Promising Flavonoids with Chemopreventive Potential
- Review, Var, NA
NRF2↑, fisetin increased the protein level and accumulation Nrf2 and down regulated the protein levels of Keap1
Keap1↓,
ChemoSen↑, In vitro studies showed that fisetin and quercetin could also act against chemotherapeutic resistance in several cancers
BioAv↓, Fisetin has low aqueous solubility and bioavailability
Cyt‑c↑, release of cytochrome c from mitochondria, caspase-3 and caspase-9 mRNA and protein expression, and B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated X (Bax) levels, were found to be regulated in the fisetin-treated cancer cell line
Casp3↑,
Casp9↑,
BAX↑,
tumCV↓, fisetin at 5–80 µM significantly reduced the viability of A431 human epidermoid carcinoma cells by the release of cytochrome c,
Mcl-1↓, reducing the anti-apoptotic protein expression of Bcl-2, Bcl-xL, and Mcl-1 along with elevation of pro-apoptotic protein expression (Bax, Bak, and Bad) and caspase cleavage and poly-ADP-ribose polymerase (PARP) protein
cl‑PARP↑,
IGF-1↓, fisetin promoted caspase-8 and cytochrome c expression, possibly by impeding the aberrant activation of insulin growth factor receptor 1 and Akt
Akt↓,
CDK6↓, fisetin binds with CDK6, which in turn blocks its activity with an inhibitory concentration (IC50) at a concentration of 0.85 μM
TumCCA↑, fisetin is identified as a regulator of cell cycle checkpoints, leading to cell arrest through CDK inhibition in HL60 cells and astrocyte cells over the G0/G1, S, and G2/M phases
P53?, exhibiting elevated levels of p53
cycD1/CCND1↓, 10–60 μM fisetin concentration, prostate cancer cells PC3, LNCaP, and CWR22Ry1 had decreased cellular viability and decreased levels of D1, D2, and E cyclins and their activating partners CDK2, and CDKs 4/ 6,
cycE/CCNE↓,
CDK2↓, decreased levels of D1, D2, and E cyclins and their activating partners CDK2, and CDKs 4/ 6,
CDK4↓,
CDK6↓,
MMP2↓, fisetin displayed tumor inhibitory effects by blocking MMP-2 and MMP-9 at mRNA and protein levels in prostate PC-3 cells
MMP9↓,
MMP1↓, Similarly, fisetin can also inhibit MMP-1, MMP-9, MMP-7, MMP-3, and MMP-14 gene expression linked with ECM remodeling in human umbilical vascular endothelial cells (HUVECs) and HT-1080 fibrosarcoma cells [9
MMP7↓,
MMP3↓,
VEGF↓, fisetin in a concentration-dependent manner (10–50 μM concentration) significantly inhibited regular serum, growth-enhancing supplement, and vascular endothelial growth factor (VEGF)
PI3K↓, fisetin inhibited PI3K expression and phosphorylation of Akt
mTOR↓, fisetin treatment activated the apoptotic process through inhibiting both PI3K and mammalian target of rapamycin (mTOR) signaling pathways
COX2/PTGS2↓, fisetin resulted in activation of apoptosis and inhibition of COX-2 and the Wnt/EGFR/NF-kB pathway
Wnt↓,
EGFR↓,
NF-kB↓,
ERK↓, Fisetin is one of the flavonoids that has been found to suppress ERK1/2 signaling in human gastric (SGC7901), hepatic (HepG2), colorectal (Caco-2)
ROS↑, fisetin induced ROS generation and suppressed ERK through its phosphorylation
angioG↓, fisetin-induced anti-angiogenesis led to reduced VEGF and epidermal growth factor receptor (EGFR) expression
TNF-α↓, Fisetin suppressed IL-1β-mediated expression of inducible nitric oxide synthase, nitric oxide, interleukin-6, tumor necrotic factor-α, prostaglandin E2, cyclooxygenase-2 (iNOS, NO, IL-6, TNF-α, PGE2, and COX-2),
PGE2↓,
iNOS↓,
NO↓,
IL6↓,
HSP70/HSPA5↝, fisetin-mediated inhibition of cellular proliferation by HSP70 and HSP27 regulation
HSP27↝,


Showing Research Papers: 1 to 9 of 9

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 9

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

antiOx↑, 1,   GSTs↓, 1,   HO-1↑, 2,   Keap1↓, 1,   NRF2↓, 1,   NRF2↑, 3,   ROS↓, 1,   ROS↑, 5,   mt-ROS↑, 2,  

Mitochondria & Bioenergetics(tgid=3) ⓘ

CDC2↓, 1,   CDC25↓, 1,   EGF↓, 1,   MMP↓, 4,   XIAP↓, 1,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

ACC↑, 1,   AMPK↑, 2,   p‑AMPK↑, 1,   PCK1↓, 1,  

Cell Death(tgid=5) ⓘ

Akt↓, 7,   p‑Akt↓, 1,   Apoptosis↑, 1,   BAD↑, 1,   BAX↑, 3,   Bcl-2↓, 2,   BIM↑, 1,   Casp↑, 2,   Casp3↑, 3,   Casp7↑, 1,   Casp8↑, 2,   Casp9↑, 3,   Chk2↑, 1,   Cyt‑c↑, 3,   Diablo↑, 2,   DR5↑, 2,   Fas↑, 1,   IAP1↓, 1,   IAP2/BIRC3↓, 2,   iNOS↓, 1,   JNK↑, 1,   MAPK↓, 1,   MAPK↑, 1,   Mcl-1↓, 3,   Myc↓, 1,   p38↓, 1,   p38↑, 1,   p‑p38↓, 1,   survivin↓, 2,   TumCD↑, 1,  

Transcription & Epigenetics(tgid=7) ⓘ

cJun↓, 1,   p‑H3↓, 1,   tumCV↓, 3,  

Protein Folding & ER Stress(tgid=8) ⓘ

ER Stress↑, 2,   HSP27↓, 1,   HSP27↝, 1,   HSP70/HSPA5↓, 1,   HSP70/HSPA5↝, 1,   HSP90↓, 1,  

Autophagy & Lysosomes(tgid=9) ⓘ

ATG5↑, 1,   Beclin-1/ATG6↑, 1,   LC3s↑, 1,  

DNA Damage & Repair(tgid=10) ⓘ

ATM↑, 1,   CHK1↑, 1,   DNAdam↑, 1,   P53?, 1,   P53↑, 2,   cl‑PARP↑, 4,   PCNA↓, 1,  

Cell Cycle & Senescence(tgid=11) ⓘ

CDK2↓, 4,   CDK4↓, 3,   cycA1/CCNA1↓, 1,   cycD1/CCND1↓, 5,   cycE/CCNE↓, 2,   P21↑, 1,   Securin↓, 1,   TumCCA↑, 4,  

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

cFos↓, 1,   EMT↓, 3,   ERK↓, 3,   GSK‐3β↑, 1,   IGF-1↓, 1,   mTOR↓, 6,   mTORC1↓, 2,   mTORC2↓, 1,   mTORC2↑, 1,   PI3K↓, 7,   PTEN↑, 2,   RAS↓, 1,   STAT3↓, 1,   TCF↓, 1,   TumCG↓, 3,   Wnt↓, 5,  

Migration(tgid=13) ⓘ

Ca+2↑, 2,   E-cadherin↑, 2,   FAK↓, 1,   Fibronectin↓, 1,   Ki-67↓, 1,   MET↓, 1,   MMP1↓, 4,   MMP13↓, 1,   MMP2↓, 4,   MMP3↓, 2,   MMP7↓, 4,   MMP9↓, 5,   MMPs↓, 1,   N-cadherin↓, 1,   PKCδ↓, 1,   Rho↓, 1,   Snail↓, 1,   TumCI↓, 3,   TumCMig↓, 3,   TumCP↓, 4,   TumMeta↓, 2,   Twist↓, 1,   uPA↓, 5,   Vim↓, 1,   Zeb1↓, 1,   β-catenin/ZEB1↓, 2,  

Angiogenesis & Vasculature(tgid=14) ⓘ

angioG↓, 9,   ATF4↓, 1,   EGFR↓, 6,   eNOS↓, 1,   NO↓, 1,   VEGF↓, 5,   VEGFR2/KDR/Flk1↓, 1,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

COX2/PTGS2↓, 4,   IL6↓, 1,   Inflam↓, 2,   JAK1↓, 1,   NF-kB↓, 6,   p65↓, 1,   PGE2↓, 3,   PSA↓, 1,   TNF-α↓, 2,  

Hormonal & Nuclear Receptors(tgid=20) ⓘ

CDK6↓, 2,  

Drug Metabolism & Resistance(tgid=21) ⓘ

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

Clinical Biomarkers(tgid=22) ⓘ

EGFR↓, 6,   IL6↓, 1,   Ki-67↓, 1,   Myc↓, 1,   PSA↓, 1,  

Functional Outcomes(tgid=23) ⓘ

chemoP↑, 1,   hepatoP↑, 1,   neuroP↑, 1,   RenoP↑, 1,   TumVol↓, 1,  
Total Targets: 154

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

antiOx↑, 4,   GSH↑, 2,   HO-1↑, 1,   NRF2↑, 2,   ROS↓, 2,  

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↓, 3,  

Functional Outcomes(tgid=23) ⓘ

chemoPv↑, 1,   memory↑, 1,   neuroP↑, 3,  
Total Targets: 12

Scientific Paper Hit Count for: angioG, angiogenesis
9 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

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