Description: <b>Sulfasalazine</b> is primarily known as an anti-inflammatory and disease‐modifying antirheumatic drug (DMARD), used for conditions such as rheumatoid arthritis and inflammatory bowel diseases (e.g., ulcerative colitis). <br>
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-Inhibit the nuclear factor kappa B (NF-κB) pathway.<br>
-Sulfasalazine has been noted to interfere with the cystine/glutamate antiporter (system x_c⁻), which can reduce glutathione levels in cancer cells, potentially making them more susceptible to oxidative stress.<br>
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-Ability to inhibit anti-oxidant production (for ProOxidant effect).<br>
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<table border="1" cellspacing="0" cellpadding="4">
<tr>
<th>Rank</th>
<th>Pathway / Target Axis</th>
<th>Direction</th>
<th>Primary Effect</th>
<th>Notes / Cancer Relevance</th>
<th>Ref</th>
</tr>
<tr>
<td>1</td>
<td>System xC− (xCT/SLC7A11 cystine–glutamate antiporter)</td>
<td>↓ cystine uptake</td>
<td>Limits cystine supply</td>
<td>Sulfasalazine is used as an xCT inhibitor; blocking cystine uptake is the core upstream action in cancer models</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/25798841/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>2</td>
<td>Glutathione biosynthesis / GSH pool</td>
<td>↓ GSH</td>
<td>Loss of redox buffering</td>
<td>In glioma cells, cystine uptake blockade by sulfasalazine leads to glutathione depletion</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/25798841/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>3</td>
<td>ROS accumulation</td>
<td>↑ ROS</td>
<td>Oxidative stress amplification</td>
<td>Glioma study: sulfasalazine increases ROS after GSH depletion (mechanistic sequence shown)</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/25798841/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>4</td>
<td>DNA damage (oxidative/genotoxic stress)</td>
<td>↑ DNA damage</td>
<td>Checkpoint/death signaling</td>
<td>Glioma study: sulfasalazine causes DNA damage as part of the ROS-driven cytotoxic cascade</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/25798841/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>5</td>
<td>Radiosensitization (oxidative vulnerability)</td>
<td>↑ radiation sensitivity</td>
<td>Enhances radiotherapy effect</td>
<td>Melanoma model: sulfasalazine decreases glutathione and synergistically enhances X-irradiation cytotoxicity</td>
<td><a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195151" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>6</td>
<td>Ferroptosis (system xC− → GSH/GPX4 vulnerability)</td>
<td>↑ ferroptotic death</td>
<td>Iron-dependent oxidative death</td>
<td>Paclitaxel-resistant uterine serous carcinoma model: sulfasalazine (xCT inhibitor) induces ferroptotic cell death signatures</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC7400102/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>7</td>
<td>Mitochondrial apoptosis (caspase pathway)</td>
<td>↑ apoptosis</td>
<td>Programmed cell death</td>
<td>Osteosarcoma work: sulfasalazine blocks system xC− and induces cell death consistent with ferroptosis/apoptosis programs (apoptosis markers reported in the paper’s mechanism set)</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC12361513/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>8</td>
<td>NF-κB activation (IκBα degradation / IKK activity)</td>
<td>↓ NF-κB activation</td>
<td>Reduced pro-survival/inflammatory transcription</td>
<td>Mechanistic paper shows sulfasalazine blocks NF-κB activation by inhibiting IκBα degradation via IKK inhibition</td>
<td><a href="https://www.gastrojournal.org/article/S0016-5085%2800%2902308-8/fulltext" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>9</td>
<td>NF-κB nuclear translocation</td>
<td>↓ nuclear NF-κB</td>
<td>Transcriptional shutdown</td>
<td>Colon cancer cells: sulfasalazine prevents TNFα-induced NF-κB nuclear translocation and NF-κB–dependent transcription</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC508669/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>10</td>
<td>Chemo-sensitization via xCT inhibition</td>
<td>↑ chemo sensitivity (context-dependent)</td>
<td>Combination benefit</td>
<td>Mechanistic rationale: xCT inhibition lowers GSH and oxidative defense, increasing sensitivity to cytotoxic stress (glioma + radiation shown explicitly)</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/25798841/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>11</td>
<td>Tumor growth suppression in vivo (xCT-targeted stress)</td>
<td>↓ tumor growth</td>
<td>Anti-tumor efficacy</td>
<td>Glioma xenograft model: sulfasalazine plus radiosurgery improves survival compared to control/monotherapy</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/25798841/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>12</td>
<td>Resistance axis: xCT-high / antioxidant-high tumors</td>
<td>↑ vulnerability when xCT-high</td>
<td>Targeted susceptibility</td>
<td>Endometrial/USC model: sulfasalazine shows stronger cytotoxicity in resistant (stress-adapted) cells consistent with xCT dependence</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC7400102/" target="_blank">(ref)</a></td>
</tr>
</table>