Esomeprazole Potentiates the Cytotoxic Effects of Cisplatin in Gastric Carcinoma Cells

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.