Description: <b>Fisetin</b> is a plant based flavonoid. Found in strawberries(160ug/g), apples, persimmons, onions, cucumbers, grapes.<br>
<br>
-Note <a href="tbResList.php?qv=78&tsv=1109&wNotes=on&exSp=open">half-life</a> 3-4hrs<br>
- Oral <a href="tbResList.php?qv=78&tsv=792&wNotes=on&exSp=open">BioAv</a> low (40-50%)
<br>
Pathways:<br>
<!-- ROS : MMP↓, ER Stress↑, Ca+2↑, Cyt‑c↑, Casp3↑, Casp9↑, DNAdam↑, UPR↑, cl-PARP↑-->
- induce
<a href="tbResList.php?qv=78&tsv=275&wNotes=on">ROS</a> production in cancer cells, but also known to reduce it. <br>
Also a claim
<a href="https://nestronics.ca/dbx/tbResEdit.php?rid=2855">Fisetin-Induced Reactive Oxygen Species Production Has No Effect on Apoptosis</a> in RCC cells
<br>
Also one claim (NAC 10-20mM levels) that
<a href="https://nestronics.ca/dbx/tbResEdit.php?rid=2856">NAC enhances ROS/apoptosis</a>
<br>
- ROS↑ related:
<a href="tbResList.php?qv=78&tsv=197&wNotes=on&word=MMP↓">MMP↓</a>(ΔΨm),
<a href="tbResList.php?qv=78&tsv=103&wNotes=on">ER Stress↑</a>,
<a href="tbResList.php?qv=78&tsv=459&wNotes=on">UPR↑</a>,
<a href="tbResList.php?qv=78&tsv=356&wNotes=on">GRP78↑</a>,
<a href="tbResList.php?qv=78&tsv=38&wNotes=on&word=Ca+2↑">Ca+2↑</a>,
<a href="tbResList.php?qv=78&tsv=77&wNotes=on">Cyt‑c↑</a>,
<a href="tbResList.php?qv=78&wNotes=on&word=Casp">Caspases↑</a>,
<a href="tbResList.php?qv=78&tsv=82&wNotes=on&word=DNAdam↑">DNA damage↑</a>,
<a href="tbResList.php?qv=78&tsv=239&wNotes=on">cl-PARP↑</a>,
<a href="tbResList.php?qv=78&wNotes=on&word=HSP">HSP↓</a>
<br>
<!-- ANTIOXIDANT : NRF2, SOD, GSH, CAT, HO-1, GPx, GPX4, -->
- Does not appear to lower antioxidants in cancer cells
<br>
- Raises
<a href="tbResList.php?qv=78&tsv=1103&wNotes=on&word=antiOx↑">AntiOxidant</a>
defense in Normal Cells:
<a href="tbResList.php?qv=78&tsv=275&wNotes=on&word=ROS↓">ROS↓</a>,
<a href="tbResList.php?qv=78&tsv=226&wNotes=on&word=NRF2↑">NRF2↑</a>,
<a href="tbResList.php?qv=78&tsv=298&wNotes=on&word=SOD↑">SOD↑</a>,
<a href="tbResList.php?qv=78&tsv=137&wNotes=on&word=GSH↑">GSH↑</a>,
<a href="tbResList.php?qv=78&tsv=46&wNotes=on&word=Catalase↑">Catalase↑</a>,
<br>
<!-- INFLAMMATION : NF-kB↓, COX2↓, COX2↓ PRO-INFL CYTOKINES: IL-1β↓, TNF-α↓, IL-6↓, IL-8↓, -->
- lowers
<a href="tbResList.php?qv=78&tsv=953&wNotes=on&word=Inflam">Inflammation</a> :
<a href="tbResList.php?qv=78&tsv=214&wNotes=on&word=NF-kB↓">NF-kB↓</a>,
<a href="tbResList.php?qv=78&tsv=66&wNotes=on&word=COX2↓">COX2↓</a>,
<a href="tbResList.php?qv=78&tsv=235&wNotes=on&word=p38↓">p38↓</a>, Pro-Inflammatory Cytokines :
<a href="tbResList.php?qv=78&tsv=978&wNotes=on&word=IL1β↓">IL-1β↓</a>,
<a href="tbResList.php?qv=78&tsv=309&wNotes=on&word=TNF-α↓">TNF-α↓</a>,
<a href="tbResList.php?qv=78&tsv=158&wNotes=on&word=IL6↓">IL-6↓</a>,
<br>
<!-- GROWTH/METASTASES : EMT↓, MMPs↓, MMP2↓, MMP9↓, IGF-1, uPA↓, VEGF↓, ERK↓
inhibiting metastasis-associated proteins such as ROCK1, FAK, (RhoA), NF-κB and u-PA, MMP-1 and MMP-13.-->
- inhibit Growth/Metastases :
<a href="tbResList.php?qv=78&tsv=604&wNotes=on">TumMeta↓</a>,
<a href="tbResList.php?qv=78&tsv=323&wNotes=on">TumCG↓</a>,
<a href="tbResList.php?qv=78&tsv=96&wNotes=on">EMT↓</a>,
<a href="tbResList.php?qv=78&tsv=204&wNotes=on">MMPs↓</a>,
<a href="tbResList.php?qv=78&tsv=201&wNotes=on">MMP2↓</a>,
<a href="tbResList.php?qv=78&tsv=203&wNotes=on">MMP9↓</a>,
<a href="tbResList.php?qv=78&tsv=415&wNotes=on">IGF-1↓</a>,
<a href="tbResList.php?qv=78&tsv=428&wNotes=on">uPA↓</a>,
<a href="tbResList.php?qv=78&tsv=334&wNotes=on">VEGF↓</a>,
<a href="tbResList.php?qv=78&tsv=110&wNotes=on">FAK↓</a>,
<a href="tbResList.php?qv=78&tsv=273&wNotes=on">RhoA↓</a>,
<a href="tbResList.php?qv=78&tsv=214&wNotes=on">NF-κB↓</a>,
<a href="tbResList.php?qv=78&tsv=304&wNotes=on">TGF-β↓</a>,
<a href="tbResList.php?qv=78&tsv=105&wNotes=on">ERK↓</a>
<br>
<!-- CELL CYCLE ARREST : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓, CDK6↓ -->
- cause Cell cycle arrest :
<a href="tbResList.php?qv=78&tsv=322&wNotes=on">TumCCA↑</a>,
<a href="tbResList.php?qv=78&tsv=73&wNotes=on">cyclin D1↓</a>,
<a href="tbResList.php?qv=78&tsv=378&wNotes=on">cyclin E↓</a>,
<a href="tbResList.php?qv=78&tsv=467&wNotes=on">CDK2↓</a>,
<a href="tbResList.php?qv=78&tsv=894&wNotes=on">CDK4↓</a>,
<a href="tbResList.php?qv=78&tsv=895&wNotes=on">CDK6↓</a>,
<br>
<!-- MIGRATION/INVASION : TumCMig↓, TumCI↓, FAK↓, ERK↓, -->
- inhibits Migration/Invasion :
<a href="tbResList.php?qv=78&tsv=326&wNotes=on">TumCMig↓</a>,
<a href="tbResList.php?qv=78&tsv=324&wNotes=on">TumCI↓</a>,
<a href="tbResList.php?qv=78&tsv=110&wNotes=on">FAK↓</a>,
<a href="tbResList.php?qv=78&tsv=105&wNotes=on">ERK↓</a>,
<a href="tbResList.php?qv=78&tsv=96&wNotes=on">EMT↓</a>,
<a href="tbResList.php?qv=78&tsv=1117&wNotes=on">TOP1↓</a>,
<a href="tbResList.php?qv=78&tsv=657&wNotes=on">TET1↓</a>,
<br>
<!-- GLYCOLYSIS : ATP↓, HIF-1α↓, PKM2↓, cMyc↓, PDK1↓, GLUT1↓, LDHA↓, HK2↓, Glucose↓, GlucoseCon↓, lactateProd, OXPHOS -->
- inhibits
<a href="tbResList.php?qv=78&tsv=143&wNotes=on">HIF-1α↓</a>,
<a href="tbResList.php?qv=78&tsv=35&wNotes=on">cMyc↓</a>,
<a href="tbResList.php?qv=78&tsv=906&wNotes=on">LDH↓</a>,
<a href="tbResList.php?qv=78&tsv=356&wNotes=on">GRP78↑</a>,
<br>
<!-- ANGIOGENESIS : VEGF↓, VEGFR2↓, HIF-1α↓, NOTCH↓, FGF↓, PDGF↓, EGFR↓ ITG(Integrins↓)-->
- inhibits
<a href="tbResList.php?qv=78&tsv=447&wNotes=on">angiogenesis↓</a> :
<a href="tbResList.php?qv=78&tsv=334&wNotes=on">VEGF↓</a>,
<a href="tbResList.php?qv=78&tsv=143&wNotes=on">HIF-1α↓</a>,
<a href="tbResList.php?qv=78&tsv=94&wNotes=on&word=EGFR↓">EGFR↓</a>,
<br>
<!-- CSCs : CSC↓, CK2↓, Hh↓, GLi↓, GLi1↓, -->
- inhibits Cancer Stem Cells :
<a href="tbResList.php?qv=78&tsv=677&wNotes=on">CD133↓</a>,
<a href="tbResList.php?qv=78&tsv=342&wNotes=on">β-catenin↓</a>,
<br>
<!-- OTHERS : -->
- Others: <a href="tbResList.php?qv=78&tsv=252&wNotes=on">PI3K↓</a>,
<a href="tbResList.php?qv=78&tsv=4&wNotes=on">AKT↓</a>,
<a href="tbResList.php?qv=78&wNotes=on&word=JAK">JAK↓</a>,
<a href="tbResList.php?qv=78&wNotes=on&word=STAT">STAT↓</a>,
<a href="tbResList.php?qv=78&tsv=377&wNotes=on">Wnt↓</a>,
<a href="tbResList.php?qv=78&tsv=342&wNotes=on">β-catenin↓</a>,
<a href="tbResList.php?qv=78&tsv=9&wNotes=on">AMPK↓</a>,
<a href="tbResList.php?qv=78&tsv=105&wNotes=on">ERK↓</a>,
<a href="tbResList.php?qv=78&tsv=168&wNotes=on">JNK</a>,
<br>
<!-- SYNERGIES : -->
- Synergies:
<a href="tbResList.php?qv=78&tsv=1106&wNotes=on">chemo-sensitization</a>,
<a href="tbResList.php?qv=78&tsv=1171&wNotes=on">chemoProtective</a>,
<a href="tbResList.php?qv=78&tsv=1107&wNotes=on">RadioSensitizer</a>,
<a href="tbResList.php?qv=78&tsv=961&esv=2&wNotes=on&exSp=open">Others(review target notes)</a>,
<a href="tbResList.php?qv=78&tsv=1105&wNotes=on">Neuroprotective</a>,
<a href="tbResList.php?qv=78&tsv=557&wNotes=on">Cognitive</a>,
<a href="tbResList.php?qv=78&tsv=1175&wNotes=on">Renoprotection</a>,
<a href="tbResList.php?qv=78&tsv=1179&wNotes=on">Hepatoprotective</a>,
<a href="tbResList.php?&qv=78&tsv=1188&wNotes=on">CardioProtective</a>,
<br>
<br>
<!-- SELECTIVE: -->
- Selectivity:
<a href="tbResList.php?qv=78&tsv=1110&wNotes=on">Cancer Cells vs Normal Cells</a><br>
<br>
Fisetin effect on Cancer Cells
<table border="1" cellspacing="0" cellpadding="4">
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer Cells</th>
<th>Normal Cells</th>
<th>Label</th>
<th>Primary Interpretation</th>
<th>Notes</th>
</tr>
<tr>
<td>1</td>
<td>PI3K → AKT → mTOR axis</td>
<td>↓ AKT / ↓ mTOR signaling</td>
<td>↔ adaptive suppression</td>
<td>Driver</td>
<td>Loss of survival and growth signaling</td>
<td>Fisetin consistently suppresses pro-survival PI3K/AKT signaling, supporting growth inhibition and sensitization to stress</td>
</tr>
<tr>
<td>2</td>
<td>NF-κB signaling</td>
<td>↓ NF-κB activation</td>
<td>↓ inflammatory NF-κB tone</td>
<td>Driver</td>
<td>Suppression of inflammatory survival transcription</td>
<td>NF-κB inhibition contributes to anti-inflammatory effects and reduced tumor-supportive signaling</td>
</tr>
<tr>
<td>3</td>
<td>Reactive oxygen species (ROS)</td>
<td>↑ ROS (context- & dose-dependent)</td>
<td>↓ ROS</td>
<td>Conditional Driver</td>
<td>Biphasic redox modulation</td>
<td>Fisetin can act as a pro-oxidant in cancer cells at higher stress/dose while remaining antioxidant in normal cells</td>
</tr>
<tr>
<td>4</td>
<td>Mitochondrial integrity / intrinsic apoptosis</td>
<td>↓ ΔΨm; ↑ caspase activation</td>
<td>↔ preserved</td>
<td>Secondary</td>
<td>Execution of intrinsic apoptosis</td>
<td>Mitochondrial apoptosis occurs downstream of signaling and redox disruption</td>
</tr>
<tr>
<td>5</td>
<td>Cell cycle regulation</td>
<td>↑ G1 or G2/M arrest</td>
<td>↔ spared</td>
<td>Phenotypic</td>
<td>Cytostatic growth control</td>
<td>Cell-cycle arrest reflects upstream pathway inhibition rather than direct CDK blockade</td>
</tr>
<tr>
<td>6</td>
<td>Senescence / senolytic action</td>
<td>↑ senescence clearance (senescent-like tumor/stroma subsets)</td>
<td>↓ senescent cell burden (selective)</td>
<td>Secondary</td>
<td>Selective vulnerability of senescent-like cells</td>
<td>Fisetin is commonly described as senolytic; in cancer context this may impact tumor microenvironment and therapy-induced senescence</td>
</tr>
<tr>
<td>7</td>
<td>MAPK stress signaling (JNK / p38)</td>
<td>↑ JNK / ↑ p38 (context-dependent)</td>
<td>↔ minimal</td>
<td>Secondary</td>
<td>Stress-mediated apoptosis signaling</td>
<td>MAPK activation often follows ROS increase and supports apoptotic signaling</td>
</tr>
<tr>
<td>8</td>
<td>NRF2 antioxidant response</td>
<td>↑ NRF2 (adaptive, context-dependent)</td>
<td>↑ NRF2 (protective)</td>
<td>Adaptive</td>
<td>Stress compensation</td>
<td>NRF2 activation reflects redox buffering responses rather than primary cytotoxicity</td>
</tr>
<tr>
<td>9</td>
<td>Migration / invasion (EMT, MMP axis)</td>
<td>↓ migration & invasion</td>
<td>↔</td>
<td>Phenotypic</td>
<td>Anti-metastatic phenotype</td>
<td>Reduced EMT and protease activity limit invasive behavior downstream of signaling changes</td>
</tr>
</table>