Fisetin / NO 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


NO, Nitric Oxide: Click to Expand ⟱
Source:
Type:
Once the cancer has begun, NO seems to play a protumoral role rather than antitumoral one as the concentration required to cause tumor cell cytotoxicity cannot be achieved by cancer cells.
The mechanistic roles of nitric oxide (NO) during cancer progression have been important considerations since its discovery as an endogenously generated free radical. Nonetheless, the impacts of this signaling molecule can be seemingly contradictory, being both pro-and antitumorigenic, which complicates the development of cancer treatments based on the modulation of NO fluxes in tumors. At a fundamental level, low levels of NO drive oncogenic pathways, immunosuppression, metastasis, and angiogenesis, while higher levels lead to apoptosis and reduced hypoxia and also sensitize tumors to conventional therapies. However, clinical outcome depends on the type and stage of the tumor as well as the tumor microenvironment.
Nitric oxide is generated by three main nitric oxide synthase isoforms: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS).

– In many cancers, especially under inflammatory conditions, iNOS expression is upregulated. In contrast, eNOS levels may also be altered in cancers such as breast or prostate cancer.

• Expression Patterns in Tumors:
– Elevated iNOS expression is commonly observed in various tumor types (e.g., colon, breast, lung, and melanoma) and is often associated with an inflammatory microenvironment.

– Changes in eNOS and nNOS expression have also been reported and may contribute to angiogenesis and tumor blood flow regulation.
Scientific Papers found: Click to Expand⟱
2861- FIS,    The neuroprotective effects of fisetin, a natural flavonoid in neurodegenerative diseases: Focus on the role of oxidative stress
- Review, Nor, NA - Review, Stroke, NA - Review, Park, NA
*antiOx↑, *ROS↓, *neuroP↑, *NO↑, BioAv↝, *BBB↑, *toxicity↑, *eff↑, *GSH↑, *SOD↑, *Aβ↓, *12LOX↓, *COX2↓, *Catalase↑, *Inflam↓, *TNF-α↓, *IL6↑, *lipid-P↓, NF-kB↓, IL1β↓, NRF2↑, HO-1↑, GSTs↑, cognitive↑, *BDNF↑,
2862- FIS,    Fisetin averts oxidative stress in pancreatic tissues of streptozotocin-induced diabetic rat
- in-vivo, Diabetic, NA
*BG↓, *NF-kB↓, *IL1β↓, *NO↓, *Insulin↑, *SOD↑, *Catalase↑, *GPx↑, *GSTs↑,
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↝,
2843- FIS,    Fisetin and Quercetin: Promising Flavonoids with Chemopreventive Potential
- Review, Var, NA
NRF2↑, Keap1↓, ChemoSen↑, BioAv↓, Cyt‑c↑, Casp3↑, Casp9↑, BAX↑, tumCV↓, Mcl-1↓, cl‑PARP↑, IGF-1↓, Akt↓, CDK6↓, TumCCA↑, P53?, cycD1/CCND1↓, cycE/CCNE↓, CDK2↓, CDK4↓, CDK6↓, MMP2↓, MMP9↓, MMP1↓, MMP7↓, MMP3↓, VEGF↓, PI3K↓, mTOR↓, COX2↓, Wnt↓, EGFR↓, NF-kB↓, ERK↓, ROS↑, angioG↓, TNF-α↓, PGE2↓, iNOS↓, NO↓, IL6↓, HSP70/HSPA5↝, HSP27↝,

Showing Research Papers: 1 to 4 of 4

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 4

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

GSTs↑, 1,   HO-1↑, 1,   Keap1↓, 1,   NRF2↑, 2,   ROS↓, 1,   ROS↑, 2,  

Mitochondria & Bioenergetics ⓘ

MMP↓, 1,  

Core Metabolism/Glycolysis ⓘ

AMPK↑, 1,  

Cell Death ⓘ

Akt↓, 2,   BAX↑, 1,   Casp↑, 1,   Casp3↑, 2,   Casp9↑, 2,   Cyt‑c↑, 2,   Diablo↑, 1,   iNOS↓, 1,   JNK↑, 1,   Mcl-1↓, 1,   p27↑, 1,  

Kinase & Signal Transduction ⓘ

p70S6↓, 1,  

Transcription & Epigenetics ⓘ

cJun↓, 1,   tumCV↓, 1,  

Protein Folding & ER Stress ⓘ

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

DNA Damage & Repair ⓘ

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

Cell Cycle & Senescence ⓘ

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

Proliferation, Differentiation & Cell State ⓘ

cFos↓, 1,   EMT↓, 1,   ERK↓, 1,   IGF-1↓, 1,   mTOR↓, 2,   mTORC1↓, 1,   PI3K↓, 2,   Wnt↓, 1,  

Migration ⓘ

Ca+2↑, 1,   E-cadherin↑, 1,   MMP1↓, 1,   MMP2↓, 2,   MMP3↓, 1,   MMP7↓, 1,   MMP9↓, 2,   N-cadherin↓, 1,   uPA↓, 1,   Vim↓, 1,  

Angiogenesis & Vasculature ⓘ

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

Immune & Inflammatory Signaling ⓘ

COX2↓, 2,   IL1β↓, 1,   IL6↓, 1,   NF-kB↓, 3,   PGE2↓, 2,   TNF-α↓, 1,  

Hormonal & Nuclear Receptors ⓘ

CDK6↓, 3,  

Drug Metabolism & Resistance ⓘ

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

Clinical Biomarkers ⓘ

EGFR↓, 1,   IL6↓, 1,  

Functional Outcomes ⓘ

cognitive↑, 1,  
Total Targets: 79

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

antiOx↓, 1,   antiOx↑, 1,   Catalase↑, 2,   GPx↑, 1,   GSH↑, 2,   GSTs↑, 1,   HO-1↑, 1,   lipid-P↓, 1,   NRF2↑, 1,   ROS↓, 1,   SOD↑, 2,  

Mitochondria & Bioenergetics ⓘ

Insulin↑, 1,  

Core Metabolism/Glycolysis ⓘ

12LOX↓, 1,   p‑cMyc↑, 1,  

Proliferation, Differentiation & Cell State ⓘ

ERK↑, 1,  

Angiogenesis & Vasculature ⓘ

NO↓, 1,   NO↑, 1,  

Barriers & Transport ⓘ

BBB↑, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 1,   IL1β↓, 1,   IL6↑, 1,   Inflam↓, 2,   NF-kB↓, 1,   TNF-α↓, 1,  

Synaptic & Neurotransmission ⓘ

BDNF↑, 1,  

Protein Aggregation ⓘ

Aβ↓, 1,  

Drug Metabolism & Resistance ⓘ

eff↑, 1,  

Clinical Biomarkers ⓘ

BG↓, 1,   IL6↑, 1,  

Functional Outcomes ⓘ

neuroP↑, 1,   toxicity↑, 1,  
Total Targets: 31

Scientific Paper Hit Count for: NO, Nitric Oxide
4 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#:563  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

 

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