Description: <b>Itraconazole</b> is a medication used in the management and treatment of fungal infections.<br>
<p><b>Itraconazole</b> (ITZ; brand <b>Sporanox</b>) — oral triazole antifungal (drug). Oncology relevance is mainly <b>repurposing</b> research (not an approved anticancer indication).</p>
<p><b>Primary mechanisms (conceptual rank):</b><br>
1) ↓ Ergosterol synthesis via fungal CYP51 inhibition (primary approved antifungal MoA)<br>
2) ↓ Hedgehog signaling (SMO pathway inhibition; anticancer repurposing)<br>
3) ↓ Angiogenesis / endothelial signaling (anti-angiogenic effects reported; AKT/mTOR signaling suppression in endothelium models)<br>
4) ↑ Autophagy / cell-cycle arrest (model-dependent anticancer phenotypes)</p>
<p><b>Bioavailability / PK relevance:</b> Oral bioavailability ~55%; capsules absorb best with a full meal; reduced by low gastric acidity (PPIs/H2 blockers). Strong CYP3A4 inhibitor with major drug–drug interaction burden; boxed warning/avoid in ventricular dysfunction/CHF except for serious infections.</p>
<p><b>In-vitro vs oral exposure:</b> Many anticancer in-vitro effects occur at concentrations that may exceed (or sit near the upper range of) achievable systemic exposure; clinical relevance is formulation/PK-limited and indication-specific.</p>
<p><b>Clinical evidence status:</b> Approved antifungal; oncology evidence is preclinical + small human/phase II repurposing signals (no oncology RCT approval).</p>
<br>
Cancer pathways:<br>
-inhibit VEGF<br>
-inhibit Hedghog Signaling Pathway<br>
-P-glycoprotein Inhibition<br>
-mTOR Pathway<br>
<br>
<h3>Itraconazole — 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>Hedgehog (SMO → GLI)</td>
<td>↓ (model-dependent)</td>
<td>↔</td>
<td>R/G</td>
<td>Reduced HH-driven proliferation</td>
<td>Repurposing core: inhibits SMO/HH signaling in HH-dependent tumors (e.g., BCC contexts); not an approved oncology indication.</td>
</tr>
<tr>
<td>2</td>
<td>Angiogenesis (endothelial growth signaling)</td>
<td>↓ vascular support</td>
<td>↓ endothelial proliferation (context-dependent)</td>
<td>R/G</td>
<td>Anti-angiogenic effect</td>
<td>Identified in repurposing screens as anti-angiogenic; often framed via endothelial signaling suppression (AKT/mTOR in some models).</td>
</tr>
<tr>
<td>3</td>
<td>AKT / mTOR</td>
<td>↓ (model-dependent)</td>
<td>↓ (endothelium; context-dependent)</td>
<td>R/G</td>
<td>Reduced anabolic/survival signaling</td>
<td>Reported in endothelial and some tumor models; often tied to growth inhibition and vascular effects.</td>
</tr>
<tr>
<td>4</td>
<td>Autophagy</td>
<td>↑ (model-dependent)</td>
<td>↔ / ↑ (stress-dependent)</td>
<td>R/G</td>
<td>Stress adaptation / growth arrest</td>
<td>Often described as autophagic growth arrest; can be cytostatic or contribute to death depending on context.</td>
</tr>
<tr>
<td>5</td>
<td>Cell cycle</td>
<td>↓ proliferation</td>
<td>↔</td>
<td>G</td>
<td>Checkpoint arrest</td>
<td>Phenotype reported across models; typically requires sustained exposure.</td>
</tr>
<tr>
<td>6</td>
<td>Apoptosis (intrinsic; caspases)</td>
<td>↑ (model-dependent)</td>
<td>↔ / ↑ (high exposure)</td>
<td>R/G</td>
<td>Programmed cell death</td>
<td>Usually secondary to pathway inhibition / metabolic stress; varies by tumor type and exposure.</td>
</tr>
<tr>
<td>7</td>
<td>ROS</td>
<td>↔ (not primary)</td>
<td>↔</td>
<td>P/R</td>
<td>No dominant redox program</td>
<td>ROS is not a canonical primary ITZ mechanism versus HH/angiogenesis; include only with model-specific evidence.</td>
</tr>
<tr>
<td>8</td>
<td>NRF2</td>
<td>↔</td>
<td>↔</td>
<td>R/G</td>
<td>No primary modulation</td>
<td>No consistent NRF2-first mechanism at therapeutic exposure in the repurposing literature.</td>
</tr>
<tr>
<td>9</td>
<td>Ferroptosis</td>
<td>↔ (insufficiently established)</td>
<td>↔</td>
<td>R/G</td>
<td>Not a canonical ITZ axis</td>
<td>Not a standard mechanistic claim for ITZ; treat as investigational unless a specific study supports it.</td>
</tr>
<tr>
<td>10</td>
<td>HIF-1α</td>
<td>↓ (indirect; context-dependent)</td>
<td>↔</td>
<td>G</td>
<td>Hypoxia/angiogenesis coupling reduction</td>
<td>Primarily indirect via anti-angiogenic effects; tumor hypoxia biology can be complex.</td>
</tr>
<tr>
<td>11</td>
<td>Ca²⁺ signaling</td>
<td>↔</td>
<td>↔</td>
<td>P/R</td>
<td>No primary role</td>
<td>Not a recognized primary ITZ axis.</td>
</tr>
<tr>
<td>12</td>
<td>Clinical Translation Constraint</td>
<td>↓ (constraint)</td>
<td>↓ (constraint)</td>
<td>—</td>
<td>DDIs + exposure variability</td>
<td>Major constraints: CYP3A4 inhibition (drug–drug interactions), absorption dependence on meal/acidity, CHF/ventricular dysfunction warning, and repurposing effects that may require higher exposure or specific tumor dependence (HH).</td>
</tr>
</table>
<p><b>TSF legend:</b> P: 0–30 min (direct target engagement); R: 30 min–3 hr (acute signaling shifts); G: >3 hr (gene-regulatory/phenotype outcomes)</p>