Fisetin / P21 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


P21, P21/CDKN1A: Click to Expand ⟱
Source:
Type: Proapototic
cyclin-dependent kinase inhibitor p21 (also known as p21 WAF1/Cip1) promotes cell cycle arrest in response to many stimuli.
P21 is a cyclin-dependent kinase inhibitor that plays a crucial role in regulating the cell cycle. It is encoded by the CDKN1A gene and is a key player in the cellular response to stress, including DNA damage.
P21 is often considered a tumor suppressor because its expression is upregulated in response to p53 activation, a well-known tumor suppressor protein. When DNA damage occurs, p53 can activate the transcription of the CDKN1A gene, leading to increased levels of P21, which helps prevent the proliferation of damaged cells.
In many cancers, the p53 pathway is disrupted, leading to decreased levels of P21. p21 is a apoptotic marker protein.
Cell cycle arrest gene p21
Field Suggested Entry
Target CDKN1A / p21 / p21Cip1/Waf1
Full Name Cyclin-dependent kinase inhibitor 1A
Target Class CIP/KIP-family cyclin-dependent kinase inhibitor
Main Binding Partners CDK2, CDK1, CDK4/6, cyclin complexes, PCNA
Primary Biology p53-mediated cell-cycle arrest, DNA damage response, senescence, differentiation, CDK inhibition, RB/E2F pathway suppression, apoptosis regulation
Cancer Relevance High but context-dependent: p21 can suppress tumor growth through cell-cycle arrest and senescence, but can also support apoptosis resistance, senescent-cell survival, and therapy resistance in some tumors
AD Relevance Medium: indirect relevance through neuronal cell-cycle re-entry, senescence, p53 stress signaling, and aging-related cell-cycle dysregulation
Therapeutic Direction Context-dependent. Restore/activate p21 for tumor-suppressive arrest where appropriate; inhibit or bypass p21 where it promotes apoptosis resistance, senescent-cell survival, or treatment resistance.


Scientific Papers found: Click to Expand⟱
2852- FIS,    A comprehensive view on the fisetin impact on colorectal cancer in animal models: Focusing on cellular and molecular mechanisms
- Review, CRC, NA
Risk↓, P53↑, MDM2↓, COX2↓, Wnt↓, NF-kB↓, CDK2↓, CDK4↓, p‑RB1↓, cycE/CCNE↓, P21↑, NRF2↓, ROS↑, Casp8↑, Fas↑, TRAIL↑, DR5↑, MMP↓, Cyt‑c↑, selectivity↑, P450↝, GSTs↝, RadioS↑, Inflam↓, β-catenin/ZEB1↓, EGFR↓, TumCCA↑, ChemoSen↑,
2845- FIS,    Fisetin: A bioactive phytochemical with potential for cancer prevention and pharmacotherapy
- Review, Var, NA
PI3K↓, Akt↓, mTOR↓, p38↓, *antiOx↑, *neuroP↑, Casp3↑, Bcl-2↓, Mcl-1↓, BAX↑, BIM↑, BAD↑, AMPK↑, ACC↑, DNAdam↑, MMP↓, eff↑, ROS↑, cl‑PARP↑, Cyt‑c↑, Diablo↑, P53↑, p65↓, Myc↓, HSP70/HSPA5↓, HSP27↓, COX2↓, Wnt↓, EGFR↓, NF-kB↓, TumCCA↑, CDK2↓, CDK4↓, cycD1/CCND1↓, cycA1/CCNA1↓, P21↑, MMP2↓, MMP9↓, TumMeta↓, MMP1↓, MMP3↓, MMP7↓, MET↓, N-cadherin↓, Vim↓, Snail↓, Fibronectin↓, E-cadherin↑, uPA↓, ChemoSen↑, EMT↓, Twist↓, Zeb1↓, cFos↓, cJun↓, EGF↓, angioG↓, VEGF↓, eNOS↓, *NRF2↑, HO-1↑, NRF2↓, GSTs↓, ATF4↓,
2859- FIS,    The Natural Flavonoid Fisetin Inhibits Cellular Proliferation of Hepatic, Colorectal, and Pancreatic Cancer Cells through Modulation of Multiple Signaling Pathways
- in-vitro, Liver, HepG2 - NA, Colon, Caco-2
TumCG↓, other↝, Casp3↑, Casp7↑, PGE2↓, GSTs↓, Wnt↓, EGFR↓, NF-kB↓, COX2↓, P53↑, P21↑, P450↓,
2825- FIS,    Exploring the molecular targets of dietary flavonoid fisetin in cancer
- Review, Var, NA
*Inflam↓, *antiOx↓, *ERK↑, *p‑cMyc↑, *NRF2↑, *GSH↑, *HO-1↑, mTOR↓, PI3K↓, Akt↓, TumCCA↑, cycD1/CCND1↓, cycE/CCNE↓, CDK2↓, CDK4↓, CDK6↓, P21↑, p27↑, JNK↑, MMP2↓, MMP9↓, uPA↓, NF-kB↓, cFos↓, cJun↓, E-cadherin↑, Vim↓, N-cadherin↓, EMT↓, MMP↓, Cyt‑c↑, Diablo↑, Casp↑, cl‑PARP↑, P53↑, COX2↓, PGE2↓, HSP70/HSPA5↓, HSP27↓, DNAdam↑, Casp3↑, Casp9↑, ROS↑, AMPK↑, NO↑, Ca+2↑, mTORC1↓, p70S6↓, ROS↓, ER Stress↑, IRE1↑, ATF4↑, GRP78/BiP↑, eff↑, eff↑, eff↑, RadioS↑, ChemoSen↑, Half-Life↝,
2828- FIS,    Fisetin, a Potent Anticancer Flavonol Exhibiting Cytotoxic Activity against Neoplastic Malignant Cells and Cancerous Conditions: A Scoping, Comprehensive Review
- Review, Var, NA
*neuroP↑, *antiOx↑, *Inflam↓, RenoP↑, COX2↓, Wnt↓, EGFR↓, NF-kB↓, Casp3↑, Ca+2↑, Casp8↑, TumCCA↑, CDK1↓, PI3K↓, Akt↓, mTOR↓, MAPK↓, *P53↓, *P21↓, *p16↓, mTORC1↓, mTORC2↓, P53↑, P21↑, cycD1/CCND1↓, cycA1/CCNA1↓, CDK2↓, CDK4↓, BAX↑, Bcl-2↓, PCNA↓, HER2/EBBR2↓, Cyt‑c↑, MMP↓, cl‑Casp9↑, MMP2↓, MMP9↓, cl‑PARP↑, uPA↓, DR4↑, DR5↑, ROS↓, AIF↑, CDC25↓, Dose↑, CHOP↑, ROS↑, cMyc↓, cardioP↑,
2832- FIS,    Fisetin's Promising Antitumor Effects: Uncovering Mechanisms and Targeting for Future Therapies
- Review, Var, NA
MMP↓, mtDam↑, Cyt‑c↑, Diablo↑, Casp↑, cl‑PARP↑, Bak↑, BIM↑, Bcl-xL↓, Bcl-2↓, P53↑, ROS↑, AMPK↑, Casp9↑, Casp3↑, BID↑, AIF↑, Akt↓, mTOR↓, MAPK↓, Wnt↓, β-catenin/ZEB1↓, TumCCA↑, P21↑, p27↑, cycD1/CCND1↓, cycE/CCNE↓, CDK2↓, CDK4↓, CDK6↓, TumMeta↓, uPA↓, E-cadherin↑, Vim↓, EMT↓, Twist↓, DNAdam↑, ROS↓, COX2↓, PGE2↓, HSF1↓, cFos↓, cJun↓, AP-1↓, Mcl-1↓, NF-kB↓, IRE1↑, ER Stress↑, ATF4↑, GRP78/BiP↑, MMP2↓, MMP9↓, TCF-4↓, MMP7↓, RadioS↑, TOP1↓, TOP2↓,
2839- FIS,    Dietary flavonoid fisetin for cancer prevention and treatment
- Review, Var, NA
DNAdam↑, ROS↑, Apoptosis↑, Bcl-2↓, BAX↑, cl‑Casp9↑, cl‑Casp3↑, Cyt‑c↑, lipid-P↓, TumCG↓, TumCA↓, TumCMig↓, TumCI↓, uPA↓, ERK↓, MMP9↓, NF-kB↓, cFos↓, cJun↓, AP-1↓, TumCCA↑, AR↓, mTORC1↓, mTORC2↓, TSC2↑, EGF↓, TGF-β↓, EMT↓, P-gp↓, PI3K↓, Akt↓, mTOR↓, eff↑, ROS↓, ER Stress↑, IRE1↑, ATF4↑, GRP78/BiP↑, ChemoSen↑, CDK2↓, CDK4↓, cycE/CCNE↓, cycD1/CCND1↓, P21↑, COX2↓, Wnt↓, EGFR↓, β-catenin/ZEB1↓, TCF-4↓, MMP7↓, RadioS↑, eff↑,

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) ⓘ

GSTs↓, 2,   GSTs↝, 1,   HO-1↑, 1,   lipid-P↓, 1,   NRF2↓, 2,   ROS↓, 4,   ROS↑, 6,  

Mitochondria & Bioenergetics(tgid=3) ⓘ

AIF↑, 2,   CDC25↓, 1,   EGF↓, 2,   MMP↓, 5,   mtDam↑, 1,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

ACC↑, 1,   AMPK↑, 3,   cMyc↓, 1,  

Cell Death(tgid=5) ⓘ

Akt↓, 5,   Apoptosis↑, 1,   BAD↑, 1,   Bak↑, 1,   BAX↑, 3,   Bcl-2↓, 4,   Bcl-xL↓, 1,   BID↑, 1,   BIM↑, 2,   Casp↑, 2,   Casp3↑, 5,   cl‑Casp3↑, 1,   Casp7↑, 1,   Casp8↑, 2,   Casp9↑, 2,   cl‑Casp9↑, 2,   Cyt‑c↑, 6,   Diablo↑, 3,   DR4↑, 1,   DR5↑, 2,   Fas↑, 1,   JNK↑, 1,   MAPK↓, 2,   Mcl-1↓, 2,   MDM2↓, 1,   Myc↓, 1,   p27↑, 2,   p38↓, 1,   TRAIL↑, 1,  

Kinase & Signal Transduction(tgid=6) ⓘ

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

Transcription & Epigenetics(tgid=7) ⓘ

cJun↓, 4,   other↝, 1,  

Protein Folding & ER Stress(tgid=8) ⓘ

CHOP↑, 1,   ER Stress↑, 3,   GRP78/BiP↑, 3,   HSF1↓, 1,   HSP27↓, 2,   HSP70/HSPA5↓, 2,   IRE1↑, 3,  

DNA Damage & Repair(tgid=10) ⓘ

DNAdam↑, 4,   P53↑, 6,   cl‑PARP↑, 4,   PCNA↓, 1,  

Cell Cycle & Senescence(tgid=11) ⓘ

CDK1↓, 1,   CDK2↓, 6,   CDK4↓, 6,   cycA1/CCNA1↓, 2,   cycD1/CCND1↓, 5,   cycE/CCNE↓, 4,   P21↑, 7,   p‑RB1↓, 1,   TumCCA↑, 6,  

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

cFos↓, 4,   EMT↓, 4,   ERK↓, 1,   mTOR↓, 5,   mTORC1↓, 3,   mTORC2↓, 2,   PI3K↓, 4,   TCF-4↓, 2,   TOP1↓, 1,   TOP2↓, 1,   TumCG↓, 2,   Wnt↓, 6,  

Migration(tgid=13) ⓘ

AP-1↓, 2,   Ca+2↑, 2,   E-cadherin↑, 3,   Fibronectin↓, 1,   MET↓, 1,   MMP1↓, 1,   MMP2↓, 4,   MMP3↓, 1,   MMP7↓, 3,   MMP9↓, 5,   N-cadherin↓, 2,   Snail↓, 1,   TGF-β↓, 1,   TumCA↓, 1,   TumCI↓, 1,   TumCMig↓, 1,   TumMeta↓, 2,   Twist↓, 2,   uPA↓, 5,   Vim↓, 3,   Zeb1↓, 1,   β-catenin/ZEB1↓, 3,  

Angiogenesis & Vasculature(tgid=14) ⓘ

angioG↓, 1,   ATF4↓, 1,   ATF4↑, 3,   EGFR↓, 5,   eNOS↓, 1,   NO↑, 1,   VEGF↓, 1,  

Barriers & Transport(tgid=15) ⓘ

P-gp↓, 1,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

COX2↓, 7,   Inflam↓, 1,   NF-kB↓, 7,   p65↓, 1,   PGE2↓, 3,  

Hormonal & Nuclear Receptors(tgid=20) ⓘ

AR↓, 1,   CDK6↓, 2,  

Drug Metabolism & Resistance(tgid=21) ⓘ

ChemoSen↑, 4,   Dose↑, 1,   eff↑, 6,   Half-Life↝, 1,   P450↓, 1,   P450↝, 1,   RadioS↑, 4,   selectivity↑, 1,  

Clinical Biomarkers(tgid=22) ⓘ

AR↓, 1,   EGFR↓, 5,   HER2/EBBR2↓, 1,   Myc↓, 1,  

Functional Outcomes(tgid=23) ⓘ

cardioP↑, 1,   RenoP↑, 1,   Risk↓, 1,  
Total Targets: 133

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

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

Core Metabolism/Glycolysis(tgid=4) ⓘ

p‑cMyc↑, 1,  

DNA Damage & Repair(tgid=10) ⓘ

p16↓, 1,   P53↓, 1,  

Cell Cycle & Senescence(tgid=11) ⓘ

P21↓, 1,  

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

ERK↑, 1,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

Inflam↓, 2,  

Functional Outcomes(tgid=23) ⓘ

neuroP↑, 2,  
Total Targets: 12

Scientific Paper Hit Count for: P21, P21/CDKN1A
7 Fisetin
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#:234  State#:%  Dir#:2
  wNotes=0  sortOrder:rid,rpid

 

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