Description: <p><b>Niclosamide</b> (brand: <b>Niclocide</b>; NIC) — salicylanilide anthelmintic (tapeworm drug) being investigated for <b>drug repurposing</b> in oncology due to multi-pathway signaling inhibition and mitochondrial/energy-stress effects. Sources: Rx/essential-medicines antiparasitic; multiple repurposing reviews.</p>
<p><b>Primary mechanisms (conceptual rank):</b><br>
1) Mitochondrial energy disruption (uncoupling / ATP depletion; AMPK-linked energy stress)<br>
2) Wnt/β-catenin inhibition (LRP6/β-catenin axis; stemness/CSC phenotypes)<br>
3) STAT3 inhibition (anti-survival transcription)<br>
4) mTORC1 suppression (growth/anabolism ↓; autophagy context)<br>
5) NF-κB / Notch modulation (context-dependent; anti-inflammatory/anti-survival)</p>
<p><b>Bioavailability / PK relevance:</b> <b>Poor solubility and low/variable oral systemic exposure</b> are major constraints; formulation work (e.g., solution approaches) is used to improve reproducibility/systemic availability.</p>
<p><b>In-vitro vs oral exposure:</b> Many anticancer effects are observed at concentrations that can exceed typical systemic exposure from standard oral dosing (qualifier: <i>high concentration only</i> for direct tumor cytotoxicity in many models).</p>
<p><b>Clinical evidence status:</b> Approved antiparasitic; oncology remains <b>preclinical + early/small human repurposing studies</b> (no established oncology RCT approval/indication).</p>
<h3>Niclosamide (Niclocide) — Cancer vs Normal Cell Pathway Map</h3>
<table border="1" cellpadding="4" cellspacing="0">
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer Cells</th>
<th>Normal Cells</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
<tr>
<td>1</td>
<td>Mitochondrial energy metabolism (OXPHOS uncoupling / ATP)</td>
<td>↓ ATP (primary; dose-dependent)</td>
<td>↓ ATP (high concentration only)</td>
<td>P/R</td>
<td>Energy stress → growth inhibition</td>
<td>Core pharmacology includes mitochondrial/energy disruption; can trigger downstream stress signaling.</td>
</tr>
<tr>
<td>2</td>
<td>Wnt/β-catenin (LRP6/β-catenin; CSC/stemness)</td>
<td>↓ (model-dependent)</td>
<td>↔</td>
<td>R/G</td>
<td>Reduced proliferation / stemness programs</td>
<td>Frequently highlighted in repurposing; relevant in Wnt-driven or CSC-enriched contexts.</td>
</tr>
<tr>
<td>3</td>
<td>STAT3</td>
<td>↓</td>
<td>↔</td>
<td>R/G</td>
<td>Anti-survival transcription blockade</td>
<td>Often positioned as a central anti-tumor axis and combination-sensitization mechanism.</td>
</tr>
<tr>
<td>4</td>
<td>mTORC1 / growth-anabolism</td>
<td>↓</td>
<td>↔ / ↓ (stress-dependent)</td>
<td>R/G</td>
<td>Reduced anabolic signaling</td>
<td>Frequently co-reported with Wnt/STAT3 inhibition; can couple to autophagy responses.</td>
</tr>
<tr>
<td>5</td>
<td>AMPK (energy-stress sensor)</td>
<td>↑ (context-dependent)</td>
<td>↑ (stress-dependent)</td>
<td>R</td>
<td>Catabolic shift / growth suppression</td>
<td>Often downstream of ATP depletion; can antagonize mTORC1 signaling.</td>
</tr>
<tr>
<td>6</td>
<td>NF-κB</td>
<td>↓ (context-dependent)</td>
<td>↓ (context-dependent)</td>
<td>R/G</td>
<td>Reduced inflammatory / survival programs</td>
<td>Not always dominant; varies by model and inflammatory dependence.</td>
</tr>
<tr>
<td>7</td>
<td>Notch</td>
<td>↓ (model-dependent)</td>
<td>↔</td>
<td>G</td>
<td>Differentiation / stemness modulation</td>
<td>Reported in repurposing literature; often secondary to broader stress/signaling effects.</td>
</tr>
<tr>
<td>8</td>
<td>ROS</td>
<td>↑ (dose-dependent)</td>
<td>↔ / ↑ (high concentration only)</td>
<td>P/R</td>
<td>Oxidative stress contribution</td>
<td>Can be downstream of mitochondrial disruption; may contribute to cytotoxicity or resistance depending on context.</td>
</tr>
<tr>
<td>9</td>
<td>NRF2 (protective vs resistance role)</td>
<td>↔ / ↑ (adaptive; context-dependent)</td>
<td>↔ / ↑ (adaptive)</td>
<td>R/G</td>
<td>Stress-response adjustment</td>
<td>Typically secondary; may reduce sensitivity if antioxidant adaptation dominates.</td>
</tr>
<tr>
<td>10</td>
<td>Autophagy</td>
<td>↑ or ↓ (context-dependent)</td>
<td>↔ / ↑ (stress-dependent)</td>
<td>R/G</td>
<td>Stress adaptation vs cell-death coupling</td>
<td>Often described as a stress-response phenotype; can be cytostatic or pro-death depending on tumor context.</td>
</tr>
<tr>
<td>11</td>
<td>Ca²⁺ signaling</td>
<td>↔ (stress-related)</td>
<td>↔</td>
<td>P/R</td>
<td>No primary axis</td>
<td>Not a canonical primary target; include only if a specific model shows ER/mitochondrial Ca²⁺ disruption.</td>
</tr>
<tr>
<td>12</td>
<td>Clinical Translation Constraint</td>
<td>↓ (constraint)</td>
<td>↓ (constraint)</td>
<td>—</td>
<td>Exposure variability + formulation dependence</td>
<td>Poor solubility/low systemic exposure and high variability with oral dosing drive repurposing limitations; solution/formulation approaches aim to increase systemic availability.</td>
</tr>
</table>
<p><b>TSF legend:</b> P: 0–30 min; R: 30 min–3 hr; G: >3 hr</p>