Description: <b>Ivermectin</b> , Medicationthat treats some parasitic diseases<br>
<p><b>Ivermectin</b> (IVM; brands include <b>Stromectol</b>; Rx antiparasitic) — a macrocyclic lactone anthelmintic used for certain parasitic infections. Oncology relevance is primarily <b>repurposing</b> research (preclinical + early trials), not an approved anticancer indication.</p>
<p><b>Primary mechanisms (conceptual rank):</b><br>
1) <b>Parasite MoA:</b> glutamate-gated Cl⁻ channel modulation → paralysis/death (invertebrate-selective)<br>
2) <b>Repurposing (cancer):</b> multi-pathway inhibition (Wnt/β-catenin ↓; STAT3 ↓; PI3K/AKT/mTOR ↓; PAK1-linked signaling ↓; model-dependent)<br>
3) Tumor cell stress programs (autophagy/apoptosis ↑; context-dependent)<br>
4) Tumor microenvironment/immune modulation (context-dependent; exploratory)</p>
<p><b>Bioavailability / PK relevance:</b> Oral; half-life ~18 h; primarily CYP3A4 metabolism; excretion mainly fecal. High-fat meal can increase bioavailability (~2.5× reported in product monograph). CNS exposure is normally limited by <b>P-glycoprotein</b> at the BBB (risk increases if P-gp function is impaired or inhibited).</p>
<p><b>In-vitro vs oral exposure:</b> Many reported anticancer effects use concentrations that may exceed typical systemic exposure from standard antiparasitic dosing (<i>high concentration only</i> for direct tumor cytotoxicity in many models).</p>
<p><b>Clinical evidence status:</b> Approved antiparasitic; oncology evidence = preclinical + small/early human studies (no oncology RCT approval/indication).</p>
<h3>Ivermectin — 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>Wnt/β-catenin</td>
<td>↓ (model-dependent)</td><td>↔</td><td>R/G</td>
<td>Reduced proliferation / stemness programs</td>
<td>Frequently cited repurposing axis; relevance highest in Wnt-dependent contexts.</td>
</tr>
<tr>
<td>2</td><td>STAT3</td>
<td>↓ (model-dependent)</td><td>↔</td><td>R/G</td>
<td>Anti-survival transcription blockade</td>
<td>Often presented as a central anti-tumor signaling node in repurposing literature.</td>
</tr>
<tr>
<td>3</td><td>PI3K/AKT/mTOR</td>
<td>↓ (model-dependent)</td><td>↔</td><td>R/G</td>
<td>Reduced anabolic survival signaling</td>
<td>Commonly co-reported with Wnt/STAT3 effects; may contribute to cytostatic phenotypes.</td>
</tr>
<tr>
<td>4</td><td>PAK1-linked signaling</td>
<td>↓ (model-dependent)</td><td>↔</td><td>R/G</td>
<td>Reduced migration / growth signaling</td>
<td>Repurposing reviews highlight PAK1 as a putative node; tumor-type dependence is high.</td>
</tr>
<tr>
<td>5</td><td>Autophagy</td>
<td>↑ or ↔ (context-dependent)</td><td>↔ / ↑ (stress-dependent)</td><td>R/G</td>
<td>Stress adaptation vs growth suppression</td>
<td>Often cytostatic; can support survival or contribute to death depending on context.</td>
</tr>
<tr>
<td>6</td>
<td>Glycolysis / Warburg (glucose uptake, lactate output)</td>
<td>↓ (model-dependent; secondary to energy stress; high concentration only)</td>
<td>↔ / ↓ (high concentration only)</td>
<td>R/G</td>
<td>Reduced glycolytic flux / lactate production</td>
<td>Often downstream of mitochondrial ATP stress and PI3K/AKT/mTOR inhibition; not a uniformly demonstrated primary ivermectin target and typically requires higher experimental exposure.</td>
</tr>
<tr>
<td>7</td><td>Apoptosis (intrinsic; caspases)</td>
<td>↑ (model-dependent; high concentration only)</td><td>↔ / ↑ (high exposure)</td><td>R/G</td>
<td>Programmed cell death</td>
<td>Typically downstream of pathway inhibition/stress; exposure gap common.</td>
</tr>
<tr>
<td>8</td><td>ROS</td>
<td>↑ or ↔ (context-dependent)</td><td>↔</td><td>P/R</td>
<td>Secondary stress contributor</td>
<td>Not a canonical primary target; can emerge downstream of stress signaling.</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>Secondary; could blunt efficacy if antioxidant adaptation dominates.</td>
</tr>
<tr>
<td>10</td><td>HIF-1α</td>
<td>↔ / ↓ (model-dependent)</td><td>↔</td><td>G</td>
<td>Not a consistent primary axis</td>
<td>Reported variably; treat as secondary unless tumor model is hypoxia-driven.</td>
</tr>
<tr>
<td>11</td><td>Ferroptosis</td>
<td>↔ (insufficiently established)</td><td>↔</td><td>R/G</td>
<td>Not canonical</td>
<td>Not a standard ivermectin-first claim; include only with specific supporting studies.</td>
</tr>
<tr>
<td>12</td><td>Ca²⁺ signaling</td>
<td>↔</td><td>↔</td><td>P/R</td>
<td>No primary role</td>
<td>Include only if a model explicitly measures Ca²⁺/ER-stress endpoints.</td>
</tr>
<tr>
<td>13</td><td>Clinical Translation Constraint</td>
<td>↓ (constraint)</td><td>↓ (constraint)</td><td>—</td>
<td>Exposure + evidence + BBB safety context</td>
<td>Most tumor-directed effects are preclinical and often high-concentration. PK/food effects (high-fat meal ↑ exposure), CYP3A4 metabolism, and P-gp BBB protection (neurotoxicity risk if impaired/inhibited) are key constraints; oncology trials remain early.</td>
</tr>
</table>
<p><b>TSF legend:</b><br>
P: 0–30 min (primary/rapid effects)<br>
R: 30 min–3 hr (acute signaling/stress response)<br>
G: >3 hr (gene-regulatory/phenotype outcomes)</p>