Fisetin / GSK‐3β 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 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


GSK‐3β, Glycogen synthase kinase (GSK)3β: Click to Expand ⟱
Source:
Type:
GSK3β is a crucial member of the Wnt/β-catenin-, hedgehog (Hh)-, notch- and c-myc-mediated major pro-oncogenic pathways, while also being a negative regulator of epithelial–mesenchymal transition (EMT). Accumulating evidence defines GSK3β as a potential therapeutic target in cancer, thus encouraging the development of GSK3β inhibitors for cancer treatment.
Glycogen synthase kinase 3 beta (GSK-3β) is a serine/threonine kinase that plays a crucial role in various cellular processes, including cell proliferation, differentiation, and apoptosis. Its expression and activity have been implicated in several types of cancer, often with varying prognostic implications.

In many cancers, decreased GSK-3β activity is associated with poor prognosis, while in others, increased activity may correlate with aggressive disease.


Scientific Papers found: Click to Expand⟱
2827- FIS,    The Potential Role of Fisetin, a Flavonoid in Cancer Prevention and Treatment
- Review, Var, NA
*antiOx↑, *Inflam↓, neuroP↑, hepatoP↑, RenoP↑, cycD1/CCND1↓, TumCCA↑, MMPs↓, VEGF↓, MAPK↓, NF-kB↓, angioG↓, Beclin-1↑, LC3s↑, ATG5↑, Bcl-2↓, BAX↑, Casp↑, TNF-α↓, Half-Life↓, MMP↓, mt-ROS↑, cl‑PARP↑, CDK2↓, CDK4↓, Cyt‑c↑, Diablo↑, DR5↑, Fas↑, PCNA↓, Ki-67↓, p‑H3↓, chemoP↑, Ca+2↑, Dose↝, CDC25↓, CDC2↓, CHK1↑, Chk2↑, ATM↑, PCK1↓, RAS↓, p‑p38↓, Rho↓, uPA↓, MMP7↓, MMP13↓, GSK‐3β↑, E-cadherin↑, survivin↓, VEGFR2↓, IAP2↓, STAT3↓, JAK1↓, mTORC1↓, mTORC2↓, NRF2↑,
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↓, Apoptosis↑, Casp3↑, Casp8↑, Casp9↑, BAX↑, BAD↑, Bcl-2↓, Bcl-xL↓, PI3K↓, Akt↓, ERK↓, p‑JNK↑, p‑cJun↑, p‑p38↑, ROS↑, MMP↓, mTORC1↓, PTEN↑, p‑GSK‐3β↓, GSK‐3β↑, NF-kB↓, IKKα↑, Cyt‑c↑,

Showing Research Papers: 1 to 2 of 2

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 2

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

NRF2↑, 1,   ROS↑, 1,   mt-ROS↑, 1,  

Mitochondria & Bioenergetics ⓘ

CDC2↓, 1,   CDC25↓, 1,   MMP↓, 2,  

Core Metabolism/Glycolysis ⓘ

PCK1↓, 1,  

Cell Death ⓘ

Akt↓, 1,   Apoptosis↑, 1,   BAD↑, 1,   BAX↑, 2,   Bcl-2↓, 2,   Bcl-xL↓, 1,   Casp↑, 1,   Casp3↑, 1,   Casp8↑, 1,   Casp9↑, 1,   Chk2↑, 1,   Cyt‑c↑, 2,   Diablo↑, 1,   DR5↑, 1,   Fas↑, 1,   IAP2↓, 1,   p‑JNK↑, 1,   MAPK↓, 1,   p‑p38↓, 1,   p‑p38↑, 1,   survivin↓, 1,  

Transcription & Epigenetics ⓘ

p‑cJun↑, 1,   p‑H3↓, 1,   tumCV↓, 1,  

Autophagy & Lysosomes ⓘ

ATG5↑, 1,   Beclin-1↑, 1,   LC3s↑, 1,  

DNA Damage & Repair ⓘ

ATM↑, 1,   CHK1↑, 1,   cl‑PARP↑, 1,   PCNA↓, 1,  

Cell Cycle & Senescence ⓘ

CDK2↓, 1,   CDK4↓, 1,   cycD1/CCND1↓, 1,   TumCCA↑, 1,  

Proliferation, Differentiation & Cell State ⓘ

ERK↓, 1,   GSK‐3β↑, 2,   p‑GSK‐3β↓, 1,   mTORC1↓, 2,   mTORC2↓, 1,   PI3K↓, 1,   PTEN↑, 1,   RAS↓, 1,   STAT3↓, 1,  

Migration ⓘ

Ca+2↑, 1,   E-cadherin↑, 1,   Ki-67↓, 1,   MMP13↓, 1,   MMP7↓, 1,   MMPs↓, 1,   Rho↓, 1,   uPA↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 1,   VEGF↓, 1,   VEGFR2↓, 1,  

Immune & Inflammatory Signaling ⓘ

IKKα↑, 1,   JAK1↓, 1,   NF-kB↓, 2,   TNF-α↓, 1,  

Drug Metabolism & Resistance ⓘ

Dose↝, 1,   Half-Life↓, 1,  

Clinical Biomarkers ⓘ

Ki-67↓, 1,  

Functional Outcomes ⓘ

chemoP↑, 1,   hepatoP↑, 1,   neuroP↑, 1,   RenoP↑, 1,  
Total Targets: 73

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

antiOx↑, 1,  

Immune & Inflammatory Signaling ⓘ

Inflam↓, 1,  
Total Targets: 2

Scientific Paper Hit Count for: GSK‐3β, Glycogen synthase kinase (GSK)3β
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#:385  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

 

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