Sertraline Has Anticancer Effects and Enhances the Cytotoxicity of Chemotherapeutic Agents Against Pancreatic Cancer Cells.

Sertraline, a serotonin reuptake inhibitor (SSRI), has been implicated as a drug with repurposing capacities in cancer. 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-2, AsPC-1, and MIA-PaCa-2 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-DA assay. Sertraline exhibited antiproliferative activity against PDAC cells (IC50 = 8.3-16.4 µM). When combined with gemcitabine or mitoxantrone, synergistic cytotoxicity was observed in most cell lines; however, the sertraline-gemcitabine combination demonstrated an additive effect in MIA-PaCa-2 cells. Mean CI values of 0.54 ± 0.06 and 0.80 ± 0.03 in SUIT-2 cells, 0.81 ± 0.04 and 0.79 ± 0.06 in AsPC-1 cells, and 1.06 ± 0.05 and 0.79 ± 0.05 in MIA-PaCa-2 cells, respectively. These combinations suppressed colony formation, altered the cell cycle, and enhanced apoptosis. Additionally, increased ROS generation was observed, particularly in the sertraline-gemcitabine 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-based combination strategies in pancreatic cancer.