Database Query Results : Fisetin, , JNK

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 effect on Cancer Cells
Rank Pathway / Axis Cancer Cells Normal Cells Label Primary Interpretation Notes
1 PI3K → AKT → mTOR axis ↓ AKT / ↓ mTOR signaling ↔ adaptive suppression Driver Loss of survival and growth signaling Fisetin consistently suppresses pro-survival PI3K/AKT signaling, supporting growth inhibition and sensitization to stress
2 NF-κB signaling ↓ NF-κB activation ↓ inflammatory NF-κB tone Driver Suppression of inflammatory survival transcription NF-κB inhibition contributes to anti-inflammatory effects and reduced tumor-supportive signaling
3 Reactive oxygen species (ROS) ↑ ROS (context- & dose-dependent) ↓ ROS Conditional Driver Biphasic redox modulation Fisetin can act as a pro-oxidant in cancer cells at higher stress/dose while remaining antioxidant in normal cells
4 Mitochondrial integrity / intrinsic apoptosis ↓ ΔΨm; ↑ caspase activation ↔ preserved Secondary Execution of intrinsic apoptosis Mitochondrial apoptosis occurs downstream of signaling and redox disruption
5 Cell cycle regulation ↑ G1 or G2/M arrest ↔ spared Phenotypic Cytostatic growth control Cell-cycle arrest reflects upstream pathway inhibition rather than direct CDK blockade
6 Senescence / senolytic action ↑ senescence clearance (senescent-like tumor/stroma subsets) ↓ senescent cell burden (selective) Secondary Selective vulnerability of senescent-like cells Fisetin is commonly described as senolytic; in cancer context this may impact tumor microenvironment and therapy-induced senescence
7 MAPK stress signaling (JNK / p38) ↑ JNK / ↑ p38 (context-dependent) ↔ minimal Secondary Stress-mediated apoptosis signaling MAPK activation often follows ROS increase and supports apoptotic signaling
8 NRF2 antioxidant response ↑ NRF2 (adaptive, context-dependent) ↑ NRF2 (protective) Adaptive Stress compensation NRF2 activation reflects redox buffering responses rather than primary cytotoxicity
9 Migration / invasion (EMT, MMP axis) ↓ migration & invasion ↔ Phenotypic Anti-metastatic phenotype Reduced EMT and protease activity limit invasive behavior downstream of signaling changes


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⟱
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.

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↑,
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↓, 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.

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↓, 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↓,
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

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↓,
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


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 5

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

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

Mitochondria & Bioenergetics ⓘ

MEK↓, 1,   MMP↓, 3,  

Core Metabolism/Glycolysis ⓘ

AMPK↑, 1,  

Cell Death ⓘ

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

Kinase & Signal Transduction ⓘ

p70S6↓, 1,  

Transcription & Epigenetics ⓘ

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

Protein Folding & ER Stress ⓘ

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

DNA Damage & Repair ⓘ

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

Cell Cycle & Senescence ⓘ

CDK2↓, 1,   CDK4↓, 1,   cycD1/CCND1↓, 1,   cycE/CCNE↓, 1,   P21↑, 1,   TumCCA↓, 1,   TumCCA↑, 1,  

Proliferation, Differentiation & Cell State ⓘ

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

Migration ⓘ

Ca+2↑, 2,   E-cadherin↑, 1,   FAK↓, 2,   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 ⓘ

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

Immune & Inflammatory Signaling ⓘ

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

Hormonal & Nuclear Receptors ⓘ

CDK6↓, 1,  

Drug Metabolism & Resistance ⓘ

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

Clinical Biomarkers ⓘ

EGFR↓, 1,  
Total Targets: 101

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

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

Core Metabolism/Glycolysis ⓘ

p‑cMyc↑, 1,  

Cell Death ⓘ

JNK↓, 1,  

Proliferation, Differentiation & Cell State ⓘ

ERK↑, 1,  

Migration ⓘ

MMP9↓, 1,  

Immune & Inflammatory Signaling ⓘ

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

Functional Outcomes ⓘ

AntiAge↑, 1,  
Total Targets: 16

Scientific Paper Hit Count for: JNK, c-Jun N-terminal kinase (JNK)
5 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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