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This study aimed to evaluate the anticancer efficacy of sertraline alone and in combination with chemotherapeutic agents against pancreatic ductal adenocarcinoma (PDAC) cells. Antiproliferative effects of sertraline and chemotherapeutic agents against SUIT\u20102, AsPC\u20101, and MIA\u2010PaCa\u20102 PDAC cells, either alone or in combination, were determined by MTT assay. Synergistic combinations were further evaluated by clonogenic assays, cell cycle analysis, and Hoechst 33258 apoptosis staining. Reactive oxygen species (ROS) levels were quantified using the DCFH\u2010DA assay. Sertraline exhibited antiproliferative activity against PDAC cells (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20098.3\u201316.4\u2009\u00b5M). When combined with gemcitabine or mitoxantrone, synergistic cytotoxicity was observed in most cell lines; however, the sertraline\u2013gemcitabine combination demonstrated an additive effect in MIA\u2010PaCa\u20102 cells. Mean CI values of 0.54\u2009\u00b1\u20090.06 and 0.80\u2009\u00b1\u20090.03 in SUIT\u20102 cells, 0.81\u2009\u00b1\u20090.04 and 0.79\u2009\u00b1\u20090.06 in AsPC\u20101 cells, and 1.06\u2009\u00b1\u20090.05 and 0.79\u2009\u00b1\u20090.05 in MIA\u2010PaCa\u20102 cells, respectively. These combinations suppressed colony formation, altered the cell cycle, and enhanced apoptosis. Additionally, increased ROS generation was observed, particularly in the sertraline\u2013gemcitabine combination, suggesting that oxidative stress may contribute to this interaction. Combinations with doxorubicin or cisplatin did not lead to synergism. These findings provide a rationale for further investigation of sertraline\u2010based combination strategies in pancreatic cancer.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70290","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T12:05:56Z","timestamp":1783080356000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sertraline Has Anticancer Effects and Enhances the Cytotoxicity of Chemotherapeutic Agents Against Pancreatic Cancer Cells"],"prefix":"10.1002","volume":"359","author":[{"given":"Maedeh","family":"Shahrabi","sequence":"first","affiliation":[{"name":"Medicinal and Natural Products Chemistry Research Center Shiraz University of Medical Sciences  Shiraz Iran"},{"name":"School of Pharmacy Shiraz University of Medical Sciences  Shiraz 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