Description: <b>Plumbagin</b> (5-hydroxy-2-methyl-1,4-naphthoquinone) is a naturally occurring naphthoquinone derivative.<br>
<br>
–Plumbagin can undergo redox cycling to generate reactive oxygen species (ROS)<br>
-apototosis, activation of caspases, modulation of Bax, Bcl‑2, loss of MMP.<br>
-Cell cycle arrest in cancer cells, often at the G0/G1, or G2/M phases.<br>
-May inhibit NF‑κB activation<br>
– MAPK Pathways<br>
– PI3K/Akt Pathway<br>
-Downregulation of (VEGF) and matrix metalloproteinases (MMPs).<br>
<br>
-Seems capable of raising ROS in normal and cancer cells (#2004)<br>
<br>
-ic50 cancer cells 1-10uM, normal cells >10uM<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>Oxidative stress (redox cycling)</td>
<td>↑ ROS</td>
<td>Upstream cytotoxic trigger</td>
<td>Plumbagin induces ROS; ROS generation is causally linked to cell death in cancer models</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/15264212/">(ref)</a></td>
</tr>
<tr>
<td>2</td>
<td>Mitochondrial integrity (ΔΨm)</td>
<td>↓ ΔΨm</td>
<td>Mitochondrial dysfunction</td>
<td>Loss of mitochondrial membrane potential occurs during plumbagin-induced apoptotic progression</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/15264212/">(ref)</a></td>
</tr>
<tr>
<td>3</td>
<td>Intrinsic apoptosis (caspase cascade)</td>
<td>↑ caspase-dependent apoptosis</td>
<td>Programmed cell death</td>
<td>Plumbagin triggers apoptosis in leukemia and solid tumor cells; antioxidant rescue attenuates killing</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC3163832/">(ref)</a></td>
</tr>
<tr>
<td>4</td>
<td>NF-κB signaling</td>
<td>↓ NF-κB activation</td>
<td>Reduced pro-survival / inflammatory transcription</td>
<td>Demonstrates plumbagin suppresses NF-κB signaling in tumor/immune contexts (direction explicitly shown)</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC3065107/">(ref)</a></td>
</tr>
<tr>
<td>5</td>
<td>STAT3 signaling</td>
<td>↓ STAT3 phosphorylation</td>
<td>Reduced survival & proliferation signaling</td>
<td>Plumbagin suppresses constitutive and inducible STAT3 phosphorylation in cancer cells</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC2808447/">(ref)</a></td>
</tr>
<tr>
<td>6</td>
<td>PI3K–AKT–mTOR signaling</td>
<td>↓ PI3K/AKT/mTOR activity</td>
<td>Survival pathway suppression</td>
<td>Plumbagin inhibits PI3K/AKT/mTOR signaling in cancer cells with linked apoptosis/autophagy outcomes</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC4365758/">(ref)</a></td>
</tr>
<tr>
<td>7</td>
<td>Autophagy program</td>
<td>↑ autophagy</td>
<td>Stress response (context-dependent role)</td>
<td>Plumbagin induces autophagy alongside apoptosis; pathway involvement (p38, PI3K/AKT/mTOR) is demonstrated</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC4365758/">(ref)</a></td>
</tr>
<tr>
<td>8</td>
<td>Stress MAPK (p38 MAPK)</td>
<td>↑ p38 activation</td>
<td>Stress signaling amplification</td>
<td>p38 MAPK activation is implicated in plumbagin-driven apoptosis/autophagy signaling in cancer cells</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC4365758/">(ref)</a></td>
</tr>
<tr>
<td>9</td>
<td>Cell cycle control</td>
<td>↑ G2/M (or S–G2/M) arrest</td>
<td>Proliferation blockade</td>
<td>Plumbagin induces checkpoint arrest with changes in cyclins/CDKs consistent with growth inhibition</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/18023967/">(ref)</a></td>
</tr>
<tr>
<td>10</td>
<td>Death receptor axis (TRAIL receptors DR4/DR5)</td>
<td>↑ DR4/DR5 expression</td>
<td>Sensitizes to TRAIL-mediated killing</td>
<td>Plumbagin increases DR4/DR5 and enhances TRAIL killing; NAC blocks both ROS and receptor upregulation</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC3163832/">(ref)</a></td>
</tr>
<tr>
<td>11</td>
<td>EMT / invasion programs</td>
<td>↓ EMT (anti-invasive)</td>
<td>Reduced metastasis-related phenotype</td>
<td>Plumbagin suppresses epithelial–mesenchymal transition and stemness-related markers in cancer cells</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC4599573/">(ref)</a></td>
</tr>
<tr>
<td>12</td>
<td>Angiogenesis signaling (VEGFR2/VEGF-driven endothelial responses)</td>
<td>↓ angiogenesis signaling / function</td>
<td>Anti-angiogenic effect</td>
<td>Plumbagin inhibits tumor angiogenesis via interference with VEGFR2-mediated signaling in endothelial/tumor models</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC3346245/">(ref)</a></td>
</tr>
</table>