Fisetin / JNK 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
JNK, c-Jun N-terminal kinase (JNK): Click to Expand ⟱
Source:
Type:
JNK acts synergistically with NF-κB, JAK/STAT, and other signaling molecules to exert a survival function. Janus signaling promotes cancer cell survival.
JNK, or c-Jun N-terminal kinase, is a member of the mitogen-activated protein kinase (MAPK) family. It plays a crucial role in various cellular processes, including cell proliferation, differentiation, and apoptosis (programmed cell death). JNK is activated in response to various stress signals, such as UV radiation, oxidative stress, and inflammatory cytokines.
JNK activation can promote apoptosis in cancer cells, acting as a tumor suppressor. However, in other contexts, it can promote cell survival and proliferation, contributing to tumor progression.

JNK is often unregulated in cancers, leading to increased cancer cell proliferation, survival, and resistance to apoptosis. This activation is typically associated with poor prognosis and aggressive tumor behavior.
Scientific Papers found: Click to Expand⟱
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↓,

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.

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↝,

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

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.

2844- FIS,    Fisetin, a dietary flavonoid induces apoptosis via modulating the MAPK and PI3K/Akt signalling pathways in human osteosarcoma (U-2 OS) cells
- in-vitro, OS, U2OS
tumCV↓, Fisetin at 20-100 µM effectively reduced the viability of OS cells, and induced apoptosis by signifi-cantly inducing the expression of Caspases- 3,-8 and -9 and pro-apoptotic proteins (Bax and Bad) with subsequent down-regulation of Bcl-xL and Bcl-2
Apoptosis↑,
Casp3↑,
Casp8↑,
Casp9↑,
BAX↑,
BAD↑,
Bcl-2↓,
Bcl-xL↓,
PI3K↓, inhibited PI3K/Akt pathway and ERK1/2,
Akt↓,
ERK↓,
p‑JNK↑, it caused enhanced expressions of p-JNK, p-c-Jun and p-p38
p‑cJun↑,
p‑p38↑,
ROS↑, Fisetin-induced ROS generation and decrease in mitochondrial membrane potential
MMP↓, noticeable decline of mitochondrial transmembrane potential (ΔΨm) in a dose-dependent manner
mTORC1↓, fisetin at various concentrations (20-100 μM) caused a significant (p<0.05) decrease in the level of p-Akt and mTORC1 (an important effector protein of Akt), while up-regulated PTEN.
PTEN↑,
p‑GSK‐3β↓, Level of phosphorylated glycogensynthase kinase 3ǃ (GSK3ǃ), (a serine/threonine kinase) and cyclin D1 were potentially decreased by fisetin which is in line with raised non-phosphorylated levels of GSK3ǃ
GSK‐3β↑,
NF-kB↓, Down-regualtion of NF-κB along with significant up-regulations in IκB upon fisetin treatment correlates with the down-regulation of p-Akt levels.
IKKα↑,
Cyt‑c↑, activates the efflux of cytochrome C

3372- QC,  FIS,  KaempF,    Anticancer Potential of Selected Flavonols: Fisetin, Kaempferol, and Quercetin on Head and Neck Cancers
- Review, HNSCC, NA
ROCK1↑, quercetin affects the level of RhoA and NF-κB proteins in SAS cells, and stimulates the expression of RhoA, ROCK1, and NF-κB in SAS cells [53].
TumCCA↓, inhibition of the cell cycle;
HSPs↓, inhibition of heat shock proteins;
RAS↓, inhibition of Ras protein expression.
ROS↑, fisetin induces production of reactive oxygen species (ROS), increases Ca2+ release, and decreases the mitochondrial membrane potential (Ψm) in head and neck neoplastic cells.
Ca+2↑,
MMP↓,
Cyt‑c↑, quercetin increases the expression level of cytochrome c, apoptosis inducing factor and endonuclease G
Endon↑,
MMP9↓, quercetin inhibits MMP-9 and MMP-2 expression and reduces levels of the following proteins: MMP-2, -7, -9 [49,53] and -10
MMP2↓,
MMP7↓,
MMP-10↓,
VEGF↓, as well as VEGF, NF-κB p65, iNOS, COX-2, and uPA, PI3K, IKB-α, IKB-α/β, p-IKKα/β, FAK, SOS1, GRB2, MEKK3 and MEKK7, ERK1/2, p-ERK1/2, JNK1/2, p38, p-p38, c-JUN, and pc-JUN
NF-kB↓,
p65↓,
iNOS↓,
COX2/PTGS2↓,
uPA↓,
PI3K↓,
FAK↓,
MEK↓,
ERK↓,
JNK↓,
p38↓,
cJun↓,
FOXO3↑, Quercetin causes an increase in the level of FOXO1 protein both in a dose- and time-dependent way; however, it does not affect changes in expression of FOXO3a


Showing Research Papers: 1 to 7 of 7

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 7

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

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

Mitochondria & Bioenergetics(tgid=3) ⓘ

CDC25↓, 1,   MEK↓, 1,   MMP↓, 3,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

AMPK↑, 1,  

Cell Death(tgid=5) ⓘ

Akt↓, 4,   Apoptosis↑, 2,   BAD↑, 1,   BAX↑, 1,   Bcl-2↓, 1,   Bcl-xL↓, 1,   Casp↑, 1,   Casp3↑, 3,   cl‑Casp3↑, 1,   Casp8↑, 2,   Casp9↑, 3,   Cyt‑c↑, 3,   Diablo↑, 1,   DR5↑, 1,   Endon↑, 1,   IAP1↓, 1,   IAP2/BIRC3↓, 1,   iNOS↓, 1,   JNK↓, 1,   JNK↑, 3,   p‑JNK↑, 1,   MAPK↑, 1,   Mcl-1↓, 1,   p27/CDKN1B↓, 1,   p27/CDKN1B↑, 1,   p38↓, 1,   p38↑, 1,   p‑p38↑, 1,   survivin↓, 1,   TumCD↑, 1,  

Kinase & Signal Transduction(tgid=6) ⓘ

p70S6↓, 1,  

Transcription & Epigenetics(tgid=7) ⓘ

cJun↓, 2,   p‑cJun↑, 1,   other↝, 1,   tumCV↓, 1,  

Protein Folding & ER Stress(tgid=8) ⓘ

ER Stress↑, 2,   GRP78/BiP↑, 1,   HSP27↓, 1,   HSP70/HSPA5↓, 1,   HSPs↓, 1,   IRE1↑, 1,  

Autophagy & Lysosomes(tgid=9) ⓘ

TumAuto↑, 1,  

DNA Damage & Repair(tgid=10) ⓘ

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

Cell Cycle & Senescence(tgid=11) ⓘ

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

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

cFos↓, 1,   EMT↓, 2,   ERK↓, 4,   FOXO3↑, 1,   GSK‐3β↑, 1,   p‑GSK‐3β↓, 1,   mTOR↓, 2,   mTORC1↓, 2,   PI3K↓, 5,   PTEN↑, 2,   RAS↓, 1,   STAT3↓, 1,   TumCG↓, 2,   Wnt↓, 1,  

Migration(tgid=13) ⓘ

Ca+2↑, 2,   E-cadherin↑, 1,   FAK↓, 2,   Ki-67↓, 1,   MMP-10↓, 1,   MMP2↓, 3,   MMP7↓, 1,   MMP9↓, 3,   N-cadherin↓, 1,   PKCδ↓, 1,   ROCK1↑, 1,   TumCMig↓, 1,   TumCP↓, 1,   uPA↓, 3,   Vim↓, 1,   β-catenin/ZEB1↓, 1,  

Angiogenesis & Vasculature(tgid=14) ⓘ

angioG↓, 1,   ATF4↑, 1,   EGFR↓, 2,   NO↑, 1,   VEGF↓, 2,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

COX2/PTGS2↓, 3,   IKKα↑, 1,   Inflam↓, 1,   NF-kB↓, 4,   p65↓, 1,   PGE2↓, 2,  

Hormonal & Nuclear Receptors(tgid=20) ⓘ

CDK6↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

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

Clinical Biomarkers(tgid=22) ⓘ

EGFR↓, 2,   Ki-67↓, 1,  

Functional Outcomes(tgid=23) ⓘ

TumVol↓, 1,  
Total Targets: 117

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

antiOx↓, 1,   antiOx↑, 1,   Catalase↑, 1,   GSH↑, 1,   HO-1↑, 1,   NRF2↑, 1,   ROS↓, 1,   SOD↑, 1,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

p‑cMyc↑, 1,  

Cell Death(tgid=5) ⓘ

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

DNA Damage & Repair(tgid=10) ⓘ

P53↓, 1,  

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

ERK↑, 1,  

Migration(tgid=13) ⓘ

MMP9↓, 1,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

Inflam↓, 2,   NF-kB↓, 1,   TNF-α↓, 1,  

Protein Aggregation(tgid=19) ⓘ

Aβ↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

Dose↝, 1,  

Functional Outcomes(tgid=23) ⓘ

AntiAge↑, 1,   neuroP↑, 1,  
Total Targets: 25

Scientific Paper Hit Count for: JNK, c-Jun N-terminal kinase (JNK)
7 Fisetin
1 Ascorbyl Palmitate
1 Quercetin
1 Kaempferol
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#:168  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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