Description: <b>Salinomycin</b> is a polyether ionophore antibiotic that is produced by the bacterium Streptomyces albus. It was first isolated in 1979 and has been found to have a range of biological activities, including antibacterial, antifungal, and anticancer properties.<br>
It has been shown to induce apoptosis (programmed cell death) in a range of cancer cell lines, including breast, lung, and colon cancer cells. Salinomycin has also been found to inhibit the growth of cancer stem cells.<br>
Salinomycin, a widely used antibiotic in poultry farming<br>
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Actions:
-Strong activity against cancer stem cells
-Disrupts mitochondrial ion gradients → ROS
-Non-thiol, non-NRF2 dominant
Key pathways
-Mitochondrial K⁺ dysregulation
-ROS-mediated apoptosis
-Wnt/β-catenin inhibition
Chemo relevance
-Generally compatible or synergistic
-Not a redox buffer
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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>K+ ionophore activity / ionic homeostasis</td>
<td>↑ K+ transport (ionophore) / ↓ intracellular K+ homeostasis</td>
<td>Electrochemical disruption</td>
<td>Salinomycin is directly described as a <i>potassium ionophore</i> in mechanistic studies of its anticancer effects</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC3156152/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>2</td>
<td>Cancer stem cell (CSC) fraction / stemness programs</td>
<td>↓ CSC proportion / tumor-initiating capacity</td>
<td>Selective CSC depletion</td>
<td>Landmark study showing salinomycin strongly reduces CSC proportion (e.g., >100-fold vs paclitaxel in their assay context) and inhibits tumor growth in vivo</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/19682730/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>3</td>
<td>Wnt/β-catenin signaling</td>
<td>↓</td>
<td>Loss of self-renewal signaling</td>
<td>Primary mechanistic paper identifying salinomycin as an inhibitor of the Wnt signaling cascade</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC3156152/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>4</td>
<td>Wnt co-receptor LRP6 (Wnt pathway control point)</td>
<td>↓ LRP6 / ↓ Wnt signaling</td>
<td>Wnt pathway suppression</td>
<td>Shows salinomycin suppresses LRP6 expression at concentrations relevant to growth inhibition, linking activity to Wnt/β-catenin suppression</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC4134741/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>5</td>
<td>Autophagic flux + lysosomal proteolysis</td>
<td>↓ autophagic flux (blocked) / ↓ lysosomal proteolytic activity</td>
<td>Abortive autophagy / stress accumulation</td>
<td>Demonstrates salinomycin blocks autophagic flux and lysosomal proteolytic activity in breast cancer CSC and non-CSC populations</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC3669181/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>6</td>
<td>ER stress / UPR (ATF4 → CHOP/DDIT3)</td>
<td>↑ ER stress / ↑ CHOP axis</td>
<td>Proteotoxic stress signaling</td>
<td>Shows salinomycin stimulates ER stress and mediates autophagy through the ATF4–CHOP–TRIB3 axis</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC3722315/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>7</td>
<td>AKT–mTOR survival signaling (via TRIB3)</td>
<td>↓ AKT / ↓ mTOR signaling</td>
<td>Reduced survival + altered autophagy control</td>
<td>Same mechanistic work links ER stress activation to TRIB3-mediated inhibition of AKT1–mTOR signaling after salinomycin exposure</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC3722315/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>8</td>
<td>ROS generation and ROS-linked lysosomal dysfunction</td>
<td>↑ ROS</td>
<td>Oxidative stress amplification</td>
<td>Demonstrates salinomycin-induced ROS and connects ROS to lysosomal membrane permeability and impaired autophagy flux</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC5058706/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>9</td>
<td>Mitochondrial apoptosis (caspase cascade)</td>
<td>↑ Caspase-9/3 activation</td>
<td>Programmed cell death</td>
<td>Shows salinomycin triggers caspase-dependent apoptosis involving caspases (including 9 and 3) in a salinomycin toxicity/mechanism study (demonstrates directionality for caspase activation)</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC3168989/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>10</td>
<td>EMT phenotype</td>
<td>↑ E-cadherin / ↓ vimentin (EMT suppressed)</td>
<td>Reduced migration/invasion</td>
<td>Reports salinomycin increases epithelial markers and decreases mesenchymal markers in a dose-dependent manner, with reduced migration/invasion</td>
<td><a href="https://www.dovepress.com/salinomycin-repressed-the-epithelialndashmesenchymal-transition--of-ep-peer-reviewed-fulltext-article-OTT" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>11</td>
<td>ABC transporter–mediated multidrug resistance</td>
<td>↓ functional MDR phenotype</td>
<td>Overcomes drug resistance</td>
<td>Directly reports salinomycin overcomes ABC transporter–mediated multidrug/apoptosis resistance in leukemia stem cell–like cells</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/20350531/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>12</td>
<td>Ferroptosis susceptibility (GPX4 axis) in CSC context</td>
<td>↑ ferroptosis (context-dependent)</td>
<td>Non-apoptotic oxidative death modality</td>
<td>Reports salinomycin induces ferroptosis in a CSC context via a pathway converging on GPX4/GPX activity regulation (directionality: ferroptosis induction by salinomycin in that model)</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/38182558/" target="_blank">(ref)</a></td>
</tr>
</table>