Description: <b>Disulfiram</b> is a synthetic small-molecule drug best known for its use in the treatment of chronic alcohol use disorder. It is a thiuram disulfide compound with the chemical formula C₁₀H₂₀N₂S₄ and acts primarily as an aldehyde dehydrogenase (ALDH) inhibitor.
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Main Actions:
-Potent copper-dependent pro-oxidant
-Targets ALDH⁺ cancer stem cells
-Strong clinical repurposing interest
Key pathways
-Cu-mediated redox cycling
-Proteasome inhibition
-Mitochondrial ROS
Chemo relevance
-Often synergistic
-Highly mechanism-dependent
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<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>Metal chelation / Disulfiram–Cu complex formation</td>
<td>↑ DSF–Cu complex formation</td>
<td>↔ limited formation</td>
<td>Driver</td>
<td>Copper-dependent cytotoxic chemistry</td>
<td>Elevated copper in cancer cells enables formation of cytotoxic DSF–Cu complexes; this is the initiating event for most anticancer effects</td>
</tr>
<tr>
<td>2</td>
<td>Proteasome / p97–NPL4 axis</td>
<td>↓ proteasome function; ↑ proteotoxic stress</td>
<td>↔ minimal disruption</td>
<td>Driver</td>
<td>Protein homeostasis collapse</td>
<td>DSF–Cu disrupts protein degradation pathways, leading to accumulation of misfolded proteins and stress signaling</td>
</tr>
<tr>
<td>3</td>
<td>Reactive oxygen species (ROS)</td>
<td>↑ ROS (metal-dependent)</td>
<td>↔ buffered</td>
<td>Secondary</td>
<td>Oxidative stress amplification</td>
<td>ROS rise follows DSF–Cu redox cycling and proteotoxic stress; not the primary trigger</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 cell death</td>
<td>Mitochondrial dysfunction and apoptosis occur downstream of proteostasis and redox stress</td>
</tr>
<tr>
<td>5</td>
<td>ALDH activity (ALDH1A1 / stemness)</td>
<td>↓ ALDH activity</td>
<td>↓ ALDH (clinically tolerated)</td>
<td>Secondary</td>
<td>Cancer stem-like cell targeting</td>
<td>ALDH inhibition preferentially impacts cancer stem-like populations; normal cells tolerate inhibition at therapeutic exposure</td>
</tr>
<tr>
<td>6</td>
<td>NF-κB signaling</td>
<td>↓ NF-κB activation</td>
<td>↓ inflammatory NF-κB tone</td>
<td>Secondary</td>
<td>Suppression of survival transcription</td>
<td>NF-κB inhibition reflects upstream proteotoxic and redox stress rather than direct targeting</td>
</tr>
<tr>
<td>7</td>
<td>Cell cycle progression</td>
<td>↓ proliferation / ↑ arrest</td>
<td>↔ largely spared</td>
<td>Phenotypic</td>
<td>Cytostatic growth control</td>
<td>Growth inhibition reflects impaired protein turnover and metabolic stress</td>
</tr>
<tr>
<td>8</td>
<td>Apoptosis / non-apoptotic death</td>
<td>↑ apoptosis or proteotoxic death</td>
<td>↔ protected</td>
<td>Phenotypic</td>
<td>Threshold-dependent cell death</td>
<td>Cell death modality depends on copper availability and stress magnitude</td>
</tr>
</table>