Description: <b>Menadione</b> (2-methyl-1,4-naphthoquinone, also termed vitamin K3)<br>
Menadione-induced ROS generation is concentration-dependent and high concentrations trigger cell death.<br>
Clinical trials conducted on patients with prostate cancer showed that ascorbic acid-menadione produced an immediate drop in tumor cell numbers through a mechanism named autoschizis.<br>
Menadione (Vitamin K3) is a synthetic naphthoquinone compound.
It is not used as a nutritional vitamin supplement in humans due to toxicity risk (particularly hemolysis and hepatotoxicity). Historically used in animal feed.<br>
<pre>
Mechanistically, menadione functions primarily as a redox-active quinone, capable of:
-Undergoing redox cycling
-Generating reactive oxygen species (ROS)
-Inducing oxidative stress
-Interacting with glutathione (GSH) systems
-Modulating mitochondrial function
</pre>
It has been investigated in oncology research largely due to its pro-oxidant cytotoxic properties, not classical vitamin K–dependent clotting roles.<br>
<br>
<!-- Vitamin K3 (Menadione) — Time-Scale Flagged Pathway Table -->
<table border="1" cellpadding="4" cellspacing="0">
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer / Tumor Context</th>
<th>Normal Tissue Context</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
<tr>
<td>1</td>
<td>Redox cycling (quinone-mediated ROS generation)</td>
<td>ROS ↑; oxidative stress ↑; apoptosis ↑ (dose-dependent)</td>
<td>Oxidative injury risk ↑ (hemolysis, hepatotoxicity)</td>
<td>P, R</td>
<td>Primary cytotoxic mechanism</td>
<td>Menadione undergoes one-electron redox cycling, generating superoxide and hydrogen peroxide; not selective for tumor cells.</td>
</tr>
<tr>
<td>2</td>
<td>Glutathione (GSH) depletion</td>
<td>GSH ↓; redox buffering capacity ↓</td>
<td>Red cell vulnerability ↑</td>
<td>P, R</td>
<td>Redox destabilization</td>
<td>Conjugation and oxidative cycling consume GSH, amplifying oxidative stress.</td>
</tr>
<tr>
<td>3</td>
<td>Mitochondrial dysfunction</td>
<td>ΔΨm ↓; ATP ↓; apoptosis signaling ↑</td>
<td>Energy stress in normal cells possible</td>
<td>R, G</td>
<td>Mitochondria-mediated apoptosis</td>
<td>ROS and redox imbalance disrupt mitochondrial membrane potential.</td>
</tr>
<tr>
<td>4</td>
<td>DNA damage (oxidative)</td>
<td>DNA strand breaks ↑ (reported)</td>
<td>Genotoxic risk ↑</td>
<td>R, G</td>
<td>Genome instability</td>
<td>Often secondary to ROS accumulation rather than direct DNA intercalation.</td>
</tr>
<tr>
<td>5</td>
<td>Synergy with ascorbate (Vitamin C)</td>
<td>Redox cycling ↑; cytotoxicity ↑ (reported in vitro)</td>
<td>Systemic oxidative injury risk ↑</td>
<td>P, R</td>
<td>Redox amplification</td>
<td>Menadione can undergo redox cycling with ascorbate, increasing ROS production; largely preclinical data.</td>
</tr>
<tr>
<td>6</td>
<td>Topoisomerase interference (reported)</td>
<td>Topo inhibition (context-dependent)</td>
<td>↔</td>
<td>R</td>
<td>Secondary mechanism</td>
<td>Some studies report interference with topoisomerase activity, but this is not the dominant mechanism.</td>
</tr>
<tr>
<td>7</td>
<td>Hemolysis risk (G6PD vulnerability)</td>
<td>—</td>
<td>Red blood cell destruction risk ↑</td>
<td>R</td>
<td>Major toxicity constraint</td>
<td>Menadione can cause hemolytic anemia, especially in G6PD deficiency.</td>
</tr>
<tr>
<td>8</td>
<td>Hepatotoxicity</td>
<td>—</td>
<td>Liver injury risk ↑</td>
<td>G</td>
<td>Clinical toxicity constraint</td>
<td>Historical reason for discontinuation as a human supplement.</td>
</tr>
<tr>
<td>9</td>
<td>Vitamin K–dependent clotting pathway</td>
<td>Minimal physiologic role in humans</td>
<td>Not equivalent to K1/K2</td>
<td>—</td>
<td>Classification clarification</td>
<td>Menadione is a synthetic precursor; does not function identically to phylloquinone (K1) or menaquinones (K2).</td>
</tr>
</table>
<p><b>Time-Scale Flag (TSF):</b> P / R / G</p>
<ul>
<li><b>P</b>: 0–30 min (rapid redox cycling and ROS generation)</li>
<li><b>R</b>: 30 min–3 hr (mitochondrial dysfunction, DNA damage signaling)</li>
<li><b>G</b>: >3 hr (apoptosis, tissue-level toxicity outcomes)</li>
</ul>