Description: <b>Parthenolide</b> is a naturally occurring sesquiterpene lactone derived from the medicinal plant feverfew (Tanacetum parthenium). <br>
-Micheliolide (MCL) is converted readily from parthenolide (PTL), and has better stability and solubility than PTL<br>
-Parthenolide is a natural compound used to treat migraines and arthritis and found to act as a potent NF-κB signaling inhibitor.<br>
<br>
Main activities include:<br>
-Inhibition of NF-κB Signaling:<br>
-Induction of Oxidative Stress (ROS): oxidative stress can overwhelm the antioxidant defenses of the cancer cells, leading to cellular damage and death<br>
-Parthenolide can interfere with STAT3 signaling, inhibiting the transcription of genes that favor tumor growth and resistance to apoptosis.<br>
-Modulation of the MAPK/ERK Pathway:<br>
-Impact on the JNK Pathway:<br>
-Parthenolide has been shown to target cancer stem cells<br>
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<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>NF-κB DNA-binding (p65/RelA Cys38 alkylation)</td>
<td>↓ NF-κB DNA binding</td>
<td>Suppresses pro-survival transcription</td>
<td>Direct mechanism: parthenolide inhibits NF-κB most likely by alkylating p65 at Cys38, reducing DNA binding</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/11500489/">(ref)</a></td>
</tr>
<tr>
<td>2</td>
<td>Thioredoxin reductase (TrxR1 / TrxR2)</td>
<td>↓ TrxR activity</td>
<td>Redox buffering collapse</td>
<td>Parthenolide directly targets TrxR1/TrxR2 (selenocysteine-containing enzymes) and inhibits function</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/27002142/">(ref)</a></td>
</tr>
<tr>
<td>3</td>
<td>ROS accumulation (superoxide / oxidative stress)</td>
<td>↑ ROS</td>
<td>Upstream cytotoxic trigger</td>
<td>Same TrxR-targeting study shows TrxR inhibition shifts redox state and drives ROS accumulation leading to apoptosis</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/27002142/">(ref)</a></td>
</tr>
<tr>
<td>4</td>
<td>Mitochondrial integrity (ΔΨm)</td>
<td>↓ ΔΨm</td>
<td>Mitochondrial dysfunction</td>
<td>Parthenolide increases ROS and is reported with a combined ΔΨm reduction accompanying apoptosis across cancer cell lines</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/37298119/">(ref)</a></td>
</tr>
<tr>
<td>5</td>
<td>Intrinsic apoptosis (caspase-3 activation)</td>
<td>↑ caspase-3</td>
<td>Programmed cell death</td>
<td>Parthenolide treatment associated with mitochondrial membrane depolarization and caspase-3 activation in cancer cells</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/19949351/">(ref)</a></td>
</tr>
<tr>
<td>6</td>
<td>STAT3 signaling (via JAK2 covalent inhibition)</td>
<td>↓ STAT3 phosphorylation/signaling</td>
<td>Reduced survival / migration programs</td>
<td>Parthenolide covalently modifies JAK2 cysteines, suppressing kinase activity and inhibiting STAT3 signaling</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/29921758/">(ref)</a></td>
</tr>
<tr>
<td>7</td>
<td>AML stem cell targeting (LSC vulnerability; regimen context)</td>
<td>↓ AML stem cell survival</td>
<td>Stem/progenitor depletion</td>
<td>Parthenolide-based regimen (parthenolide + 2DG + temsirolimus) demonstrates potent targeting of AML stem cells</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC5063982/">(ref)</a></td>
</tr>
<tr>
<td>8</td>
<td>In vivo anti-tumor effect (xenograft; parthenolide analog evidence)</td>
<td>↓ tumor growth</td>
<td>Demonstrated efficacy (derivative)</td>
<td>Note: this is for an orally bioavailable parthenolide analog (DMAPT), not native parthenolide</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC2234793/">(ref)</a></td>
</tr>
</table>