Description: <p><b>Sanguinarine</b> (SANG) — a benzophenanthridine alkaloid isolated primarily from Sanguinaria canadensis (bloodroot) and other Papaveraceae species. Potent redox-active, DNA-intercalating phytochemical studied extensively in preclinical oncology.</p>
<p><b>Primary mechanisms (conceptual rank):</b><br>
1) ROS generation → mitochondrial apoptosis<br>
2) NF-κB / STAT3 inhibition (anti-survival signaling)<br>
3) Cell-cycle arrest (G0/G1 or G2/M depending on model)<br>
4) MAPK modulation (JNK activation; ERK suppression context-dependent)<br>
5) Epigenetic/DNA interaction effects</p>
<p><b>Bioavailability / PK relevance:</b> Limited human PK data; rapid reactivity and protein binding likely restrict systemic exposure. Toxicity (oral mucosal injury, cytotoxicity) limits therapeutic window.</p>
<p><b>In-vitro vs oral exposure:</b> Many anti-cancer effects occur at micromolar concentrations unlikely achievable systemically via safe oral dosing (qualifier: high concentration only for direct cytotoxicity).</p>
<p><b>Clinical evidence status:</b> Preclinical oncology only; no validated RCT cancer indication. Safety concerns limit development.</p>
<b>Extracted</b> from bloodroot plant from whose scientific name, Sanguinaria canadensis, its name is derived; the Mexican prickly poppy; Chelidonium majus; and Macleaya cordata.<br>
<br>
<h3>Sanguinarine — 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>ROS / Mitochondrial redox stress</td>
<td>↑ (primary; dose-dependent)</td>
<td>↑ (high concentration only)</td>
<td>P/R</td>
<td>Oxidative stress → apoptosis</td>
<td>Central mechanism; rapid ROS generation drives mitochondrial membrane depolarization and cytochrome c release.</td>
</tr>
<tr>
<td>2</td>
<td>Intrinsic apoptosis (Bax↑, Bcl-2↓, caspases)</td>
<td>↑</td>
<td>↑ (high concentration only)</td>
<td>R/G</td>
<td>Programmed cell death</td>
<td>Often ROS-dependent; cancer cells show greater susceptibility due to higher basal oxidative stress.</td>
</tr>
<tr>
<td>3</td>
<td>NF-κB signaling</td>
<td>↓</td>
<td>↓ (context-dependent)</td>
<td>R/G</td>
<td>Reduced pro-survival transcription</td>
<td>Suppresses inflammatory and anti-apoptotic gene expression; contributes to anti-proliferative effect.</td>
</tr>
<tr>
<td>4</td>
<td>STAT3 axis</td>
<td>↓</td>
<td>↔</td>
<td>R/G</td>
<td>Reduced survival signaling</td>
<td>STAT3 inhibition reported in multiple tumor models; linked to decreased proliferation and invasion.</td>
</tr>
<tr>
<td>5</td>
<td>MAPK (JNK↑ / ERK↓ context-dependent)</td>
<td>↑ JNK; ↓ ERK</td>
<td>↔ / ↑ stress (high dose)</td>
<td>P/R</td>
<td>Stress-activated apoptosis signaling</td>
<td>JNK activation promotes apoptosis; ERK suppression reduces proliferation.</td>
</tr>
<tr>
<td>6</td>
<td>Cell Cycle (Cyclin D1, CDK regulation)</td>
<td>↓ proliferation</td>
<td>↔</td>
<td>G</td>
<td>G0/G1 or G2/M arrest</td>
<td>Checkpoint enforcement varies by tumor type and dose.</td>
</tr>
<tr>
<td>7</td>
<td>NRF2 axis</td>
<td>↓ (overwhelmed by ROS; context-dependent)</td>
<td>↑ (adaptive; low dose)</td>
<td>R/G</td>
<td>Redox defense modulation</td>
<td>Low dose may activate adaptive NRF2; higher doses override antioxidant defenses in cancer cells.</td>
</tr>
<tr>
<td>8</td>
<td>Ca²⁺ / ER stress</td>
<td>↑ (stress-dependent)</td>
<td>↑ (high concentration only)</td>
<td>P/R</td>
<td>ER-mitochondrial stress coupling</td>
<td>Calcium dysregulation contributes to apoptosis cascade.</td>
</tr>
<tr>
<td>9</td>
<td>Ferroptosis</td>
<td>↑ (lipid ROS-linked; investigational)</td>
<td>↔</td>
<td>R/G</td>
<td>Lipid peroxidation stress</td>
<td>ROS-driven lipid damage suggests ferroptosis overlap but not primary established mechanism.</td>
</tr>
<tr>
<td>10</td>
<td>HIF-1α</td>
<td>↓ (model-dependent)</td>
<td>↔</td>
<td>G</td>
<td>Reduced hypoxia adaptation</td>
<td>Reported suppression in some tumor contexts.</td>
</tr>
<tr>
<td>11</td>
<td>Clinical Translation Constraint</td>
<td>↓ (constraint)</td>
<td>↓ (constraint)</td>
<td>—</td>
<td>Toxicity + limited PK data</td>
<td>Oral toxicity and narrow therapeutic index limit systemic development.</td>
</tr>
</table>
<p><b>TSF legend:</b><br>
P: 0–30 min (primary redox interactions)<br>
R: 30 min–3 hr (acute stress signaling)<br>
G: >3 hr (gene-regulatory / phenotype outcomes)</p>