Ash Ashwagandha(Withaferin A)
Description: <b>Withaferin A</b> is a steroidal lactone derived from the medicinal plant Withania somnifera (commonly known as Ashwagandha).<br>
The main active constituents of Ashwagandha leaves are alkaloids and steroidal lactones (commonly known as Withanolides).<br>
-The main constituents of ashwagandha are withanolides such as withaferin A, alkaloids, steroidal lactones, tropine, and cuscohygrine.<br>
Ashwagandha is an herb that may reduce stress, anxiety, and insomnia.<br>
*-Ashwagandha is often characterized as an antioxidant.<br>
-Some studies suggest that while ashwagandha may protect normal cells from oxidative damage, it can simultaneously stress cancer cells by tipping their redox balance toward cytotoxicity.<br>
Pathways:<br>
-Induction of Apoptosis and ROS Generation<br>
-Hsp90 Inhibition and Proteasomal Degradation<br>
<br>
Cell culture studies vary widely, typically ranging from low micromolar (e.g., 1–10 µM).<br>
In animal models (commonly mice), Withaferin A has been administered in doses ranging from approximately 2 to 10 mg/kg body weight.<br>
- General wellness, Ashwagandha supplements are sometimes taken in doses ranging from 300 mg to 600 mg of an extract (often standardized to contain a certain percentage of withanolides) once or twice daily.<br>
- 400mg of WS extract was given 3X/day to schizophrenia patients. report#2001.<br>
- Ashwagandha Pure 400mg/capsule is available from mcsformulas.com.<br>
<br>
-Note <a href="tbResList.php?qv=36&tsv=1109&wNotes=on&exSp=open">half-life</a> 4-6 hrs?.<br>
<a href="tbResList.php?qv=36&tsv=792&wNotes=on&exSp=open">BioAv</a>
<br>
Pathways:<br>
<!-- ROS : MMP↓, ER Stress↑, Ca+2↑, Cyt‑c↑, Casp3↑, Casp9↑, DNAdam↑, UPR↑, cl-PARP↑-->
- well-recognized for promoting
<a href="tbResList.php?qv=36&tsv=275&wNotes=on">ROS</a> in cancer cells, while no effect(or reduction) on normal cells.<br>
- ROS↑ related:
<a href="tbResList.php?qv=36&tsv=197&wNotes=on&word=MMP↓">MMP↓</a>(ΔΨm),
<a href="tbResList.php?qv=36&tsv=103&wNotes=on">ER Stress↑</a>,
<a href="tbResList.php?qv=36&tsv=459&wNotes=on">UPR↑</a>,
<a href="tbResList.php?qv=36&tsv=356&wNotes=on">GRP78↑</a>,
<!-- <a href="tbResList.php?qv=36&tsv=38&wNotes=on&word=Ca+2↑">Ca+2↑</a>, -->
<a href="tbResList.php?qv=36&tsv=77&wNotes=on">Cyt‑c↑</a>,
<a href="tbResList.php?qv=36&wNotes=on&word=Casp">Caspases↑</a>,
<a href="tbResList.php?qv=36&tsv=82&wNotes=on&word=DNAdam↑">DNA damage↑</a>,
<a href="tbResList.php?qv=36&tsv=239&wNotes=on">cl-PARP↑</a>,
<a href="tbResList.php?qv=36&wNotes=on&word=HSP">HSP↓</a>,
<a href="tbResList.php?qv=36&wNotes=on&word=Prx">Prx</a>,<!-- mitochondrial antioxidant enzyme-->
<br>
<!-- ANTIOXIDANT : NRF2, SOD, GSH, CAT, HO-1, GPx, GPX4, -->
- Confusing results about Lowering AntiOxidant defense in Cancer Cells:
<a href="tbResList.php?qv=36&tsv=226&wNotes=on&word=NRF2↓">NRF2↓</a>,
<a href="tbResList.php?qv=36&word=Trx&wNotes=on">TrxR↓**</a>,<!-- major antioxidant system -->
<a href="tbResList.php?qv=36&tsv=298&wNotes=on&word=SOD↓">SOD↓</a>,
<a href="tbResList.php?qv=36&tsv=137&wNotes=on&word=GSH↓">GSH↓</a>
<a href="tbResList.php?qv=36&tsv=46&wNotes=on">Catalase↓</a>
<a href="tbResList.php?qv=36&tsv=597&wNotes=on">HO1↓</a>
<a href="tbResList.php?qv=36&wNotes=on&word=GPx">GPx↓</a>
<br>
- Raises
<a href="tbResList.php?qv=36&tsv=1103&wNotes=on&word=antiOx↑">AntiOxidant</a>
defense in Normal Cells:
<a href="tbResList.php?qv=36&tsv=275&wNotes=on&word=ROS↓">ROS↓</a>,
<a href="tbResList.php?qv=36&tsv=226&wNotes=on&word=NRF2↑">NRF2↑</a>,
<a href="tbResList.php?qv=36&tsv=298&wNotes=on&word=SOD↑">SOD↑</a>,
<a href="tbResList.php?qv=36&tsv=137&wNotes=on&word=GSH↑">GSH↑</a>,
<a href="tbResList.php?qv=36&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=36&tsv=953&wNotes=on&word=Inflam">Inflammation</a> :
<a href="tbResList.php?qv=36&tsv=214&wNotes=on&word=NF-kB↓">NF-kB↓</a>,
<a href="tbResList.php?qv=36&tsv=66&wNotes=on&word=COX2↓">COX2↓</a>,
<a href="tbResList.php?qv=36&tsv=235&wNotes=on&word=p38↓">p38↓</a>, Pro-Inflammatory Cytokines :
<a href="tbResList.php?qv=36&tsv=908&wNotes=on&word=NLRP3↓">NLRP3↓</a>,
<a href="tbResList.php?qv=36&tsv=978&wNotes=on&word=IL1β↓">IL-1β↓</a>,
<a href="tbResList.php?qv=36&tsv=309&wNotes=on&word=TNF-α↓">TNF-α↓</a>,
<a href="tbResList.php?qv=36&tsv=158&wNotes=on&word=IL6↓">IL-6↓</a>,
<a href="tbResList.php?qv=36&tsv=368&wNotes=on&word=IL8↓">IL-8↓</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=36&tsv=604&wNotes=on">TumMeta↓</a>,
<a href="tbResList.php?qv=36&tsv=323&wNotes=on">TumCG↓</a>,
<a href="tbResList.php?qv=36&tsv=96&wNotes=on">EMT↓</a>,
<a href="tbResList.php?qv=36&tsv=204&wNotes=on">MMPs↓</a>,
<a href="tbResList.php?qv=36&tsv=201&wNotes=on">MMP2↓</a>,
<a href="tbResList.php?qv=36&tsv=203&wNotes=on">MMP9↓</a>,
<a href="tbResList.php?qv=36&tsv=308&wNotes=on">TIMP2</a>,
<!-- <a href="tbResList.php?qv=36&tsv=415&wNotes=on">IGF-1↓</a>, -->
<a href="tbResList.php?qv=36&tsv=428&wNotes=on">uPA↓</a>,
<a href="tbResList.php?qv=36&tsv=334&wNotes=on">VEGF↓</a>,
<a href="tbResList.php?qv=36&tsv=1284&wNotes=on">ROCK1↓</a>,
<!-- <a href="tbResList.php?qv=36&tsv=110&wNotes=on">FAK↓</a>, -->
<!-- <a href="tbResList.php?qv=36&tsv=273&wNotes=on">RhoA↓</a>, -->
<a href="tbResList.php?qv=36&tsv=214&wNotes=on">NF-κB↓</a>,
<a href="tbResList.php?qv=36&tsv=79&wNotes=on">CXCR4↓</a>,
<a href="tbResList.php?qv=36&tsv=1247&wNotes=on">SDF1↓</a>,
<a href="tbResList.php?qv=36&tsv=304&wNotes=on">TGF-β↓</a>,
<a href="tbResList.php?qv=36&tsv=719&wNotes=on">α-SMA↓</a>,
<a href="tbResList.php?qv=36&tsv=105&wNotes=on">ERK↓</a>
<!-- <a href="tbResList.php?qv=36&tsv=1178&wNotes=on">MARK4↓</a> --> <!-- contributing to tumor growth, invasion, and metastasis-->
<br>
<!-- REACTIVATE GENES : HDAC↓, DNMT1↓, DNMT3A↓, EZH2↓, P53↑, -->
- reactivate genes thereby inhibiting cancer cell growth :
<a href="tbResList.php?qv=36&tsv=140&wNotes=on">HDAC↓</a>(combined with sulfor),
<a href="tbResList.php?qv=36&tsv=85&wNotes=on">DNMT1↓</a>,
<a href="tbResList.php?qv=36&tsv=86&wNotes=on">DNMT3A↓</a>,
<!-- <a href="tbResList.php?qv=36&tsv=108&wNotes=on">EZH2↓</a>, -->
<a href="tbResList.php?qv=36&tsv=236&wNotes=on">P53↑</a>,
<a href="tbResList.php?qv=36&wNotes=on&word=HSP">HSP↓</a>,
<a href="tbResList.php?qv=36&tsv=506&wNotes=on">Sp proteins↓</a>,
<a href="tbResList.php?qv=36&wNotes=on&word=TET">TET↑</a>
<br>
<!-- CELL CYCLE ARREST : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓, CDK6↓ -->
- cause Cell cycle arrest :
<a href="tbResList.php?qv=36&tsv=322&wNotes=on">TumCCA↑</a>,
<!-- <a href="tbResList.php?qv=36&tsv=73&wNotes=on">cyclin D1↓</a>, -->
<a href="tbResList.php?qv=36&tsv=378&wNotes=on">cyclin E↓</a>,
<a href="tbResList.php?qv=36&tsv=467&wNotes=on">CDK2↓</a>,
<a href="tbResList.php?qv=36&tsv=894&wNotes=on">CDK4↓</a>,
<!-- <a href="tbResList.php?qv=36&tsv=895&wNotes=on">CDK6↓</a>, -->
<br>
<!-- MIGRATION/INVASION : TumCMig↓, TumCI↓, FAK↓, ERK↓, -->
- inhibits Migration/Invasion :
<a href="tbResList.php?qv=36&tsv=326&wNotes=on">TumCMig↓</a>,
<a href="tbResList.php?qv=36&tsv=324&wNotes=on">TumCI↓</a>,
<a href="tbResList.php?qv=36&tsv=309&wNotes=on&word=TNF-α↓">TNF-α↓</a>, <!-- encourages invasion, proliferation, EMT, and angiogenesis -->
<!-- <a href="tbResList.php?qv=36&tsv=110&wNotes=on">FAK↓</a>, -->
<a href="tbResList.php?qv=36&tsv=105&wNotes=on">ERK↓</a>,
<a href="tbResList.php?qv=36&tsv=96&wNotes=on">EMT↓</a>,
<a href="tbResList.php?qv=36&tsv=1117&wNotes=on">TOP1↓</a>,
<!-- <a href="tbResList.php?qv=36&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=36&tsv=129&wNotes=on">glycolysis</a>
/<a href="tbResList.php?qv=36&tsv=947&wNotes=on">Warburg Effect</a> and
<a href="tbResList.php?qv=36&tsv=21&wNotes=on&word=ATP↓">ATP depletion</a> :
<a href="tbResList.php?qv=36&tsv=143&wNotes=on">HIF-1α↓</a>,
<a href="tbResList.php?qv=36&tsv=772&wNotes=on">PKM2↓</a>,
<a href="tbResList.php?qv=36&tsv=35&wNotes=on">cMyc↓</a>,
<a href="tbResList.php?qv=36&tsv=566&wNotes=on&word=GLUT">GLUT1↓</a>,
<a href="tbResList.php?qv=36&tsv=906&wNotes=on">LDH↓</a>,
<a href="tbResList.php?qv=36&tsv=175&wNotes=on&word=LDH">LDHA↓</a>,
<a href="tbResList.php?qv=36&tsv=773&wNotes=on">HK2↓</a>,
<!-- <a href="tbResList.php?qv=36&wNotes=on&word=PFK">PFKs↓</a>, -->
<!-- <a href="tbResList.php?qv=36&wNotes=on&word=PDK">PDKs↓</a>, -->
<!-- <a href="tbResList.php?qv=36&tsv=847&wNotes=on">ECAR↓</a>, -->
<a href="tbResList.php?qv=36&tsv=230&wNotes=on">OXPHOS↓</a>,
<a href="tbResList.php?qv=36&tsv=356&wNotes=on">GRP78↑</a>,
<!-- <a href="tbResList.php?qv=36&tsv=1278&wNotes=on">Glucose↓</a>, -->
<a href="tbResList.php?qv=36&tsv=623&wNotes=on">GlucoseCon↓</a>
<br>
<!-- ANGIOGENESIS : VEGF↓, VEGFR2↓, HIF-1α↓, NOTCH↓, FGF↓, PDGF↓, EGFR↓ ITG(Integrins↓)-->
- inhibits
<a href="tbResList.php?qv=36&tsv=447&wNotes=on">angiogenesis↓</a> :
<a href="tbResList.php?qv=36&tsv=334&wNotes=on">VEGF↓</a>,
<a href="tbResList.php?qv=36&tsv=143&wNotes=on">HIF-1α↓</a>,
<a href="tbResList.php?qv=36&wNotes=on&word=NOTCH">Notch↓</a>,
<!-- <a href="tbResList.php?qv=36&wNotes=on&word=FGF">FGF↓</a>, -->
<a href="tbResList.php?qv=36&wNotes=on&word=PDGF">PDGF↓</a>,
<a href="tbResList.php?qv=36&tsv=94&wNotes=on&word=EGFR↓">EGFR↓</a>,
<a href="tbResList.php?qv=36&&wNotes=on&word=ITG">Integrins↓</a>,
<br>
<!-- CSCs : CSC↓, CK2↓, Hh↓, GLi↓, GLi1↓, -->
- inhibits Cancer Stem Cells :
<a href="tbResList.php?qv=36&tsv=795&wNotes=on">CSC↓</a>,
<!-- <a href="tbResList.php?qv=36&tsv=524&wNotes=on">CK2↓</a>, -->
<!-- <a href="tbResList.php?qv=36&tsv=141&wNotes=on">Hh↓</a>, -->
<!-- <a href="tbResList.php?qv=36&tsv=434&wNotes=on">GLi↓</a>, -->
<!-- <a href="tbResList.php?qv=36&tsv=124&wNotes=on">GLi1↓</a>, -->
<!-- <a href="tbResList.php?qv=36&tsv=677&wNotes=on">CD133↓</a>, -->
<!-- <a href="tbResList.php?qv=36&tsv=655&wNotes=on">CD24↓</a>, -->
<a href="tbResList.php?qv=36&tsv=342&wNotes=on">β-catenin↓</a>,
<!--<a href="tbResList.php?qv=36&tsv=357&wNotes=on">n-myc↓</a>, -->
<a href="tbResList.php?qv=36&tsv=656&wNotes=on">sox2↓</a>,
<!--<a href="tbResList.php?qv=36&tsv=222&wNotes=on">notch2↓</a>, -->
<!-- <a href="tbResList.php?qv=36&tsv=1024&wNotes=on">nestin↓</a>, -->
<!-- <a href="tbResList.php?qv=36&tsv=508&wNotes=on">OCT4↓</a>, -->
<br>
<!-- OTHERS : -->
- Others: <a href="tbResList.php?qv=36&tsv=252&wNotes=on">PI3K↓</a>,
<a href="tbResList.php?qv=36&tsv=4&wNotes=on">AKT↓</a>,
<a href="tbResList.php?qv=36&wNotes=on&word=JAK">JAK↓</a>,
<a href="tbResList.php?qv=36&wNotes=on&word=STAT">STAT↓</a>,
<a href="tbResList.php?qv=36&tsv=377&wNotes=on">Wnt↓</a>,
<a href="tbResList.php?qv=36&tsv=342&wNotes=on">β-catenin↓</a>,
<a href="tbResList.php?qv=36&tsv=9&wNotes=on">AMPK</a>,
<a href="tbResList.php?qv=36&tsv=475&wNotes=on">α↓</a>,
<a href="tbResList.php?qv=36&tsv=105&wNotes=on">ERK↓</a>,
<!-- <a href="tbResList.php?qv=36&tsv=1014&wNotes=on">5↓</a>, -->
<a href="tbResList.php?qv=36&tsv=168&wNotes=on">JNK</a>,
<br>
<!-- SYNERGIES : -->
- Synergies:
<a href="tbResList.php?qv=36&tsv=1106&wNotes=on">chemo-sensitization</a>,
<a href="tbResList.php?qv=36&tsv=1171&wNotes=on">chemoProtective</a>,
<a href="tbResList.php?qv=36&tsv=1107&wNotes=on">RadioSensitizer</a>,
<a href="tbResList.php?qv=36&tsv=1185&wNotes=on">RadioProtective</a>,
<a href="tbResList.php?qv=36&tsv=961&esv=2&wNotes=on&exSp=open">Others(review target notes)</a>,
<a href="tbResList.php?qv=36&tsv=1105&wNotes=on">Neuroprotective</a>,
<a href="tbResList.php?qv=36&tsv=557&wNotes=on">Cognitive</a>,
<a href="tbResList.php?qv=36&tsv=1175&wNotes=on">Renoprotection</a>,
<a href="tbResList.php?qv=36&tsv=1179&wNotes=on">Hepatoprotective</a>,
<a href="tbResList.php?&qv=36&tsv=1188&wNotes=on">CardioProtective</a>,
<br>
<br>
<!-- SELECTIVE: -->
- Selectivity:
<a href="tbResList.php?qv=36&tsv=1110&wNotes=on">Cancer Cells vs Normal Cells</a>
<br>
<br>
<table border="1" cellspacing="0" cellpadding="4">
<tr>
<th>Rank</th>
<th>Pathway / Target Axis</th>
<th>Direction</th>
<th>Primary Effect</th>
<th>Notes / Cancer Relevance</th>
<th>Ref</th>
</tr>
<tr>
<td>1</td>
<td>Vimentin (intermediate filament) targeting</td>
<td>↓ vimentin filament integrity (covalent modification)</td>
<td>Cytoskeletal disruption; anti-migration</td>
<td>Shows withaferin A binds vimentin by covalently modifying a cysteine residue and disrupts IF organization; also linked to antiangiogenic/antitumor effects</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC3228641/">(ref)</a></td>
</tr>
<tr>
<td>2</td>
<td>NF-κB pathway (IKKβ)</td>
<td>↓ NF-κB activation (IKKβ Cys179 targeting)</td>
<td>Reduced pro-survival / inflammatory transcription</td>
<td>Demonstrates withaferin A targets Cys179 in IKKβ and inhibits NF-κB pathway activation</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/25159986/">(ref)</a></td>
</tr>
<tr>
<td>3</td>
<td>Proteasome β5 (chymotrypsin-like activity)</td>
<td>↓ proteasome activity</td>
<td>Proteotoxic stress; growth inhibition</td>
<td>Identifies tumor proteasome β5 as a primary target; shows inhibition of chymotrypsin-like activity and tumor growth reduction in xenografts</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/17093135/">(ref)</a></td>
</tr>
<tr>
<td>4</td>
<td>ROS / oxidative stress</td>
<td>↑ ROS</td>
<td>Upstream stress trigger</td>
<td>Withaferin A induces oxidative stress-mediated cytotoxicity (ROS-dependent) in oral cancer cells</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC5594071/">(ref)</a></td>
</tr>
<tr>
<td>5</td>
<td>Mitochondrial dysfunction</td>
<td>↓ ΔΨm</td>
<td>Mitochondrial failure</td>
<td>Same oral-cancer work includes mitochondrial dysfunction (ΔΨm disruption) as part of ROS-mediated killing</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC5594071/">(ref)</a></td>
</tr>
<tr>
<td>6</td>
<td>Intrinsic apoptosis</td>
<td>↑ apoptosis (caspase/PARP cleavage markers)</td>
<td>Programmed cell death</td>
<td>Withaferin A triggers apoptosis downstream of oxidative stress and mitochondrial dysfunction (apoptosis markers shown)</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC5594071/">(ref)</a></td>
</tr>
<tr>
<td>7</td>
<td>AKT / mTOR axis</td>
<td>↓ AKT / ↓ mTOR signaling</td>
<td>Reduced survival & growth signaling</td>
<td>Demonstrates inhibition of AKT/mTOR signaling axis by withaferin A in colorectal cancer model context</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC4924683/">(ref)</a></td>
</tr>
<tr>
<td>8</td>
<td>Autophagy flux (lysosomal activity)</td>
<td>↓ autophagic flux (lysosomal inhibition)</td>
<td>Energetic impairment; apoptosis coupling</td>
<td>Shows withaferin A inhibits lysosomal activity, blocks autophagic flux, and induces apoptosis in breast cancer cells</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/30698683/">(ref)</a></td>
</tr>
<tr>
<td>9</td>
<td>Angiogenesis (in vivo antiangiogenic activity)</td>
<td>↓ angiogenesis</td>
<td>Reduced tumor vascular support</td>
<td>Withaferin A is shown to be a potent inhibitor of angiogenesis in vivo (dose-responsive antiangiogenic effect)</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/15516832/">(ref)</a></td>
</tr>
<tr>
<td>10</td>
<td>ER stress / UPR linked to proteasome inhibition</td>
<td>↑ ER stress / ↑ ubiquitinated proteins</td>
<td>Proteostasis collapse</td>
<td>Withaferin A inhibits proteasome activity with accumulation of ubiquitinated proteins and ER stress/heat shock responses</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC3511540/">(ref)</a></td>
</tr>
</table>