Fisetin / Ca+2 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↑">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


Ca+2, Calcium Ion Ca+2: Click to Expand ⟱
Source:
Type:
In all eukaryotic cells, intracellular Ca2+ levels are maintained at low resting concentrations (approximately 100 nM) by the activity of the major Ca2+ extrusion system, the plasma membrane Ca2+-ATPase (PMCA), which exchanges extracellular protons (H+) for cytosolic Ca2+.
Indeed, sustained elevation of [Ca2+]C in the form of overload, saturating all Ca2+-dependent effectors, prolonged decrease in [Ca2+]ER, causing ER stress response, and high [Ca2+]M, inducing mitochondrial permeability transition (MPT), are considered to be pro-death factors.
In cancer the Ca2+-handling toolkit undergoes profound remodelling (figure 1) to favour activation of Ca2+-dependent transcription factors, such as the nuclear factor of activated T cells (NFAT), c-Myc, c-Jun, c-Fos that promote hypertrophic growth via induction of the expression of the G1 and G1/S phase transition cyclins (D and E) and associated cyclin-dependent kinases (CDK4 and CDK2).
Thus, cancer cells may evade apoptosis through decreasing calcium influx into the cytoplasm. This can be achieved by either downregulation of the expression of plasma membrane Ca2+-permeable ion channels or by reducing the effectiveness of the signalling pathways that activate these channels. Such protective measures would largely diminish the possibility of Ca2+ overload in response to pro-apoptotic stimuli, thereby impairing the effectiveness of mitochondrial and cytoplasmic apoptotic pathways.
Voltage-Gated Calcium Channels (VGCCs): Overexpression of VGCCs has been associated with increased tumor growth and metastasis in various cancers, including breast and prostate cancer.
Store-Operated Calcium Entry (SOCE): SOCE mechanisms, such as STIM1 and ORAI1, are often upregulated in cancer cells, contributing to enhanced cell survival and proliferation.
High intracellular calcium levels are associated with increased cell proliferation and migration, leading to a poorer prognosis. Calcium signaling can also influence hormone receptor status, affecting treatment responses.
Increased Ca²⁺ signaling is associated with advanced disease and metastasis. Patients with higher CaSR expression may have a worse prognosis due to enhanced tumor growth and resistance to apoptosis. -Ca2+ is an important regulator of the electric charge distribution of bio-membranes.
Scientific Papers found: Click to Expand⟱
2847- FIS,    Fisetin-induced cell death, apoptosis, and antimigratory effects in cholangiocarcinoma cells
- in-vitro, CCA, NA
tumCV↓, ChemoSen↑, TumCMig↓, ROS↑, TumCI↓, angioG↓, CDK2↓, PI3K↓, Akt↓, mTOR↓, EGFR↓, Casp↑, mTORC1↓, mTORC2↑, cycD1/CCND1↓, cycE/CCNE↓, MMP2↓, MMP9↓, ER Stress↑, Ca+2↑, eff↓,
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↝,
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↑,
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↑,
2841- FIS,    Fisetin, an Anti-Inflammatory Agent, Overcomes Radioresistance by Activating the PERK-ATF4-CHOP Axis in Liver Cancer
- in-vitro, Nor, RAW264.7 - in-vitro, Liver, HepG2 - in-vitro, Liver, Hep3B - in-vitro, Liver, HUH7
*Inflam↓, *TNF-α↓, *IL1β↓, *IL6↓, Apoptosis↓, ER Stress↑, Ca+2↑, PERK↑, ATF4↑, CHOP↑, GRP78/BiP↑, tumCV↓, LDH↑, Casp3↑, cl‑Casp3↑, cl‑Casp8↑, cl‑Casp9↑, p‑eIF2α↑, RadioS↑,
3372- QC,  FIS,  KaempF,    Anticancer Potential of Selected Flavonols: Fisetin, Kaempferol, and Quercetin on Head and Neck Cancers
- Review, HNSCC, NA
ROCK1↑, TumCCA↓, HSPs↓, RAS↓, ROS↑, Ca+2↑, MMP↓, Cyt‑c↑, Endon↑, MMP9↓, MMP2↓, MMP7↓, MMP-10↓, VEGF↓, NF-kB↓, p65↓, iNOS↓, COX2↓, uPA↓, PI3K↓, FAK↓, MEK↓, ERK↓, JNK↓, p38↓, cJun↓, FOXO3↑,

Showing Research Papers: 1 to 6 of 6

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 6

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

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

Mitochondria & Bioenergetics ⓘ

AIF↑, 1,   CDC2↓, 1,   CDC25↓, 2,   MEK↓, 1,   MMP↓, 4,  

Core Metabolism/Glycolysis ⓘ

AMPK↑, 1,   cMyc↓, 1,   LDH↑, 1,   PCK1↓, 1,  

Cell Death ⓘ

Akt↓, 3,   Apoptosis↓, 1,   BAX↑, 2,   Bcl-2↓, 2,   Casp↑, 3,   Casp3↑, 3,   cl‑Casp3↑, 1,   Casp8↑, 1,   cl‑Casp8↑, 1,   Casp9↑, 1,   cl‑Casp9↑, 2,   Chk2↑, 1,   Cyt‑c↑, 4,   Diablo↑, 2,   DR4↑, 1,   DR5↑, 2,   Endon↑, 1,   Fas↑, 1,   IAP2↓, 1,   iNOS↓, 1,   JNK↓, 1,   JNK↑, 1,   MAPK↓, 2,   p27↑, 1,   p38↓, 1,   p‑p38↓, 1,   survivin↓, 1,  

Kinase & Signal Transduction ⓘ

HER2/EBBR2↓, 1,   p70S6↓, 1,  

Transcription & Epigenetics ⓘ

cJun↓, 2,   p‑H3↓, 1,   tumCV↓, 2,  

Protein Folding & ER Stress ⓘ

CHOP↑, 2,   p‑eIF2α↑, 1,   ER Stress↑, 3,   GRP78/BiP↑, 2,   HSP27↓, 1,   HSP70/HSPA5↓, 1,   HSPs↓, 1,   IRE1↑, 1,   PERK↑, 1,  

Autophagy & Lysosomes ⓘ

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

DNA Damage & Repair ⓘ

ATM↑, 1,   CHK1↑, 1,   DNAdam↑, 1,   P53↑, 2,   cl‑PARP↑, 3,   PCNA↓, 2,  

Cell Cycle & Senescence ⓘ

CDK1↓, 1,   CDK2↓, 4,   CDK4↓, 3,   cycA1/CCNA1↓, 1,   cycD1/CCND1↓, 4,   cycE/CCNE↓, 2,   P21↑, 2,   TumCCA↓, 1,   TumCCA↑, 3,  

Proliferation, Differentiation & Cell State ⓘ

cFos↓, 1,   EMT↓, 1,   ERK↓, 1,   FOXO3↑, 1,   GSK‐3β↑, 1,   mTOR↓, 3,   mTORC1↓, 4,   mTORC2↓, 2,   mTORC2↑, 1,   PI3K↓, 4,   RAS↓, 2,   STAT3↓, 1,   Wnt↓, 1,  

Migration ⓘ

Ca+2↑, 6,   E-cadherin↑, 2,   FAK↓, 1,   Ki-67↓, 1,   MMP-10↓, 1,   MMP13↓, 1,   MMP2↓, 4,   MMP7↓, 2,   MMP9↓, 4,   MMPs↓, 1,   N-cadherin↓, 1,   Rho↓, 1,   ROCK1↑, 1,   TumCI↓, 1,   TumCMig↓, 1,   uPA↓, 4,   Vim↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 2,   ATF4↑, 2,   EGFR↓, 2,   NO↑, 1,   VEGF↓, 2,   VEGFR2↓, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 3,   JAK1↓, 1,   NF-kB↓, 4,   p65↓, 1,   PGE2↓, 1,   TNF-α↓, 1,  

Hormonal & Nuclear Receptors ⓘ

CDK6↓, 1,  

Drug Metabolism & Resistance ⓘ

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

Clinical Biomarkers ⓘ

EGFR↓, 2,   HER2/EBBR2↓, 1,   Ki-67↓, 1,   LDH↑, 1,  

Functional Outcomes ⓘ

cardioP↑, 1,   chemoP↑, 1,   hepatoP↑, 1,   neuroP↑, 1,   RenoP↑, 2,  
Total Targets: 132

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

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

Core Metabolism/Glycolysis ⓘ

p‑cMyc↑, 1,  

DNA Damage & Repair ⓘ

p16↓, 1,   P53↓, 1,  

Cell Cycle & Senescence ⓘ

P21↓, 1,  

Proliferation, Differentiation & Cell State ⓘ

ERK↑, 1,  

Immune & Inflammatory Signaling ⓘ

IL1β↓, 1,   IL6↓, 1,   Inflam↓, 4,   TNF-α↓, 1,  

Clinical Biomarkers ⓘ

IL6↓, 1,  

Functional Outcomes ⓘ

neuroP↑, 1,  
Total Targets: 16

Scientific Paper Hit Count for: Ca+2, Calcium Ion Ca+2
6 Fisetin
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#:38  State#:%  Dir#:%
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