Description: <b>Spermidine</b> : Polyamine (natural small molecule)<br>
Sources: Found in foods like wheat germ, soybeans, mushrooms, aged cheese, and fermented foods. Typical dietary intake is ~5–20 mg/day.<br>
Primary Actions: Autophagy induction, mild ROS modulation, epigenetic regulation, and modulation of polyamine metabolism.<br>
<pre>
Pathway Effect of Spermidine
Autophagy (ATG genes) ↑ Induction, Beclin-1 activation
mTORC1 signaling ↓ Inhibition, promotes catabolic metabolism
p53/p21 Modulation via epigenetic changes
Polyamine metabolism Supports or stresses proliferating cells
ROS / redox balance Mild modulation; sensitizes cancer cells to ROS stress
</pre>
Context-dependent risk: High spermidine levels might support tumor growth in polyamine-addicted cancers; dose, timing, and tumor type matter.<br>
<br>
Chemo interaction: Generally compatible; not expected to block ROS-dependent therapy at oral doses.<br>
<br>
Spermidine, a biogenic polyamine that declines along with aging, shows promise in restoring antitumor immunity by enhancing mitochondrial fatty acid oxidation (FAO)<br>
<br>
Spermidine — Cancer vs Normal Cell Effects
<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>Autophagy induction (ATG program)</td>
<td>↑ autophagy → metabolic stress, growth restraint</td>
<td>↑ autophagy → cytoprotection, homeostasis</td>
<td>Driver</td>
<td>Autophagy-first mechanism</td>
<td>Spermidine robustly induces autophagy independent of mTOR inhibition; cancer cells are more vulnerable to enforced catabolism</td>
</tr>
<tr>
<td>2</td>
<td>Epigenetic regulation (histone acetylation)</td>
<td>↓ histone acetylation (via HAT inhibition)</td>
<td>↓ acetylation (adaptive)</td>
<td>Driver</td>
<td>Chromatin-mediated transcriptional reprogramming</td>
<td>Spermidine inhibits histone acetyltransferase activity, promoting a pro-autophagic, anti-proliferative transcriptional state</td>
</tr>
<tr>
<td>3</td>
<td>Polyamine metabolism / homeostasis</td>
<td>Disrupted polyamine balance</td>
<td>Homeostatic buffering</td>
<td>Driver</td>
<td>Metabolic vulnerability</td>
<td>Cancer cells are highly dependent on polyamine flux; spermidine perturbs this balance</td>
</tr>
<tr>
<td>4</td>
<td>AMPK / mTOR nutrient-sensing axis</td>
<td>↑ AMPK; ↓ mTOR signaling</td>
<td>↑ AMPK (adaptive)</td>
<td>Secondary</td>
<td>Catabolic pressure</td>
<td>Energy-sensing pathways reinforce autophagy and growth suppression</td>
</tr>
<tr>
<td>5</td>
<td>Mitochondrial function / bioenergetics</td>
<td>↓ metabolic flexibility</td>
<td>↑ mitochondrial efficiency</td>
<td>Secondary</td>
<td>Energy stress vs optimization</td>
<td>Autophagy-driven mitochondrial turnover stresses tumor bioenergetics while benefiting normal cells</td>
</tr>
<tr>
<td>6</td>
<td>Reactive oxygen species (ROS)</td>
<td>↑ ROS (secondary, stress-linked)</td>
<td>↓ ROS</td>
<td>Secondary</td>
<td>Metabolism-linked redox shift</td>
<td>ROS changes arise indirectly from autophagy and mitochondrial remodeling, not direct redox chemistry</td>
</tr>
<tr>
<td>7</td>
<td>NRF2 antioxidant response</td>
<td>↑ NRF2 (adaptive, secondary)</td>
<td>↑ NRF2 (protective)</td>
<td>Adaptive</td>
<td>Redox homeostasis reinforcement</td>
<td>NRF2 activation reflects compensatory antioxidant signaling rather than a cytotoxic mechanism</td>
</tr>
<tr>
<td>8</td>
<td>Cell cycle / proliferation</td>
<td>↓ proliferation / ↑ arrest</td>
<td>↔ spared</td>
<td>Phenotypic</td>
<td>Cytostatic growth limitation</td>
<td>Growth inhibition reflects sustained autophagy and epigenetic effects</td>
</tr>
<tr>
<td>9</td>
<td>Apoptosis sensitivity</td>
<td>↑ sensitivity to apoptosis (context-dependent)</td>
<td>↓ apoptosis</td>
<td>Phenotypic</td>
<td>Threshold-dependent cell death</td>
<td>Apoptosis occurs when catabolic stress exceeds adaptive capacity</td>
</tr>
</table>