Esomeprazole Potentiates the Cytotoxic Effects of Cisplatin in Gastric Carcinoma Cells

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Proton pump inhibitors (PPIs), including esomeprazole, impact the acidic tumor microenvironment, potentially influencing cancer cell behavior. By examining the combined effects of esomeprazole and cisplatin on SNU-1 gastric carcinoma cells, this study sought to elucidate the mechanisms through which esomeprazole enhances cisplatin's cytotoxicity, potentially allowing for effective treatment with reduced cisplatin dosages. SNU-1 cells were treated with varying doses of esomeprazole and cisplatin, alone and in combination. Cell viability was assessed using the XTT assay. Oxidative stress (TAS/TOS), apoptosis (Annexin V, cleaved PARP), mitochondrial membrane potential, and DNA damage (8-oxo-dG, γH2AX, ATM) were evaluated using flow cytometry and ELISA. Statistical significance was determined by ANOVA. Esomeprazole alone showed no significant effect on SNU-1 cell viability, oxidative stress (TAS/TOS), apoptosis, mitochondrial membrane potential, or DNA damage. Cisplatin, however, significantly reduced cell viability (IC50 = 3.024 µg/mL), increased oxidative stress (decreased TAS, increased TOS), diminished apoptosis (increased Annexin V binding and cleaved PARP levels), disrupted mitochondrial membrane potential, and caused significant DNA damage (increased H2AX and ATM phosphorylation, and elevated 8-oxo-dG) (p < 0.001). Notably, the combination of esomeprazole and cisplatin synergistically enhanced cisplatin's effects. The combination resulted in a significantly greater reduction in cell viability (CI < 1), a further increase in oxidative stress, a higher level of apoptosis, amplified mitochondrial depolarization, and potentiated DNA damage compared to cisplatin alone (p < 0.001). Esomeprazole potentiates cisplatin-induced cytotoxicity in SNU-1 gastric cancer cells by enhancing oxidative stress, apoptosis, mitochondrial dysfunction, and DNA damage. This suggests a potential therapeutic strategy to improve cisplatin efficacy and overcome resistance in gastric cancer.