Fisetin / GSH 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↑">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


GSH, Glutathione: Click to Expand ⟱
Source:
Type:
Glutathione (GSH) is a thiol antioxidant that scavenges reactive oxygen species (ROS), resulting in the formation of oxidized glutathione (GSSG). Decreased amounts of GSH and a decreased GSH/GSSG ratio in tissues are biomarkers of oxidative stress.
Glutathione is a powerful antioxidant found in every cell of the body, composed of three amino acids: cysteine, glutamine, and glycine. It plays a crucial role in protecting cells from oxidative stress, detoxifying harmful substances, and supporting the immune system.
cancer cells can have elevated levels of glutathione, which may help them survive in the oxidative environment created by the immune response and chemotherapy. This can make cancer cells more resistant to treatment.
While glutathione can be obtained from certain foods (like fruits, vegetables, and meats), its absorption from supplements is debated. Some people take N-acetylcysteine (NAC) or other precursors to boost glutathione levels, but the effects on cancer prevention or treatment are still being studied.
Depleting glutathione (GSH) to raise reactive oxygen species (ROS) is a strategy that has been explored in cancer research and therapy.
Many cancer cells have altered redox states and may rely on GSH to survive. Increasing ROS levels can induce stress in these cells, potentially leading to cell death.
Certain drugs and compounds can deplete GSH levels. For example, agents like buthionine sulfoximine (BSO) inhibit the synthesis of GSH, leading to its depletion.
Cancer cells tend to exhibit higher levels of intracellular GSH, possibly as an adaptive response to a higher metabolism and thus higher steady-state levels of reactive oxygen species (ROS).

"...intracellular glutathione (GSH) exhibits an astounding antioxidant activity in scavenging reactive oxygen species (ROS)..."
"Cancer cells have a high level of GSH compared to normal cells."
"...cancer cells are affluent with high antioxidant levels, especially with GSH, whose appearance at an elevated concentration of ∼10 mM (10 times less in normal cells) detoxifies the cancer cells." "Therefore, GSH depletion can be assumed to be the key strategy to amplify the oxidative stress in cancer cells, enhancing the destruction of cancer cells by fruitful cancer therapy."

The loss of GSH is broadly known to be directly related to the apoptosis progression.


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↑,
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↝,

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

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

Mitochondria & Bioenergetics

MMP↓, 1,  

Core Metabolism/Glycolysis

AMPK↑, 1,  

Cell Death

Akt↓, 1,   Casp↑, 1,   Casp3↑, 1,   Casp9↑, 1,   Cyt‑c↑, 1,   Diablo↑, 1,   JNK↑, 1,   p27↑, 1,  

Kinase & Signal Transduction

p70S6↓, 1,  

Transcription & Epigenetics

cJun↓, 1,  

Protein Folding & ER Stress

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

DNA Damage & Repair

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

Cell Cycle & Senescence

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

Proliferation, Differentiation & Cell State

cFos↓, 1,   EMT↓, 1,   mTOR↓, 1,   mTORC1↓, 1,   PI3K↓, 1,  

Migration

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

Angiogenesis & Vasculature

ATF4↑, 1,   NO↑, 1,  

Immune & Inflammatory Signaling

COX2↓, 1,   IL1β↓, 1,   NF-kB↓, 2,   PGE2↓, 1,  

Hormonal & Nuclear Receptors

CDK6↓, 1,  

Drug Metabolism & Resistance

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

Functional Outcomes

cognitive↑, 1,  
Total Targets: 56

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress

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

Core Metabolism/Glycolysis

12LOX↓, 1,   p‑cMyc↑, 1,  

Proliferation, Differentiation & Cell State

ERK↑, 1,  

Angiogenesis & Vasculature

NO↑, 1,  

Barriers & Transport

BBB↑, 1,  

Immune & Inflammatory Signaling

COX2↓, 1,   IL6↑, 1,   Inflam↓, 2,   TNF-α↓, 1,  

Synaptic & Neurotransmission

BDNF↑, 1,  

Protein Aggregation

Aβ↓, 1,  

Drug Metabolism & Resistance

eff↑, 1,  

Clinical Biomarkers

IL6↑, 1,  

Functional Outcomes

neuroP↑, 1,   toxicity↑, 1,  
Total Targets: 24

Scientific Paper Hit Count for: GSH, Glutathione
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#:137  State#:%  Dir#:2
wNotes=0 sortOrder:rid,rpid

 

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