| Summary: | Background: Vacuolar ATPase (V-ATPase) is involved in cancer development. The use of proton pump inhibitors (PPIs) as V-ATPase inhibitors has been reported to enhance the effectiveness of chemotherapy in certain cancers. This study aimed to evaluate the effect of PPIs on chemotherapy for esophageal cancer. Methods: To investigate the effects of PPIs on esophageal cancer cells, human KYSE50 and 70 cells were plated and 3 PPIs (lansoprazole, esomeprazole, vonoprazan) were added at various concentrations with 5-Fluorouracil (5-FU) to the corresponding cells for a cell viability assay. To investigate the effects of PPI treatment on patients undergoing 5-FU-based therapy in the clinical setting, we retrospectively analyzed the clinical outcomes and chemotherapy-related adverse events in 40 esophageal cancer patients who received 5-FU chemotherapy in our hospital between May 2013 and April 2017. Results: In the viability assays, all PPIs significantly enhanced the cytotoxic effect of 5-FU on the two esophageal cancer cell lines. In the clinical study, PPI-treated patients showed better overall survival (OS) than patients managed without PPI treatment. A multivariate analysis revealed that PPI treatment was independently associated with OS (<i>p</i> = 0.009, HR, 0.33; 95% CI, 0.12–0.76). Conclusions: PPI treatment may safely enhance chemosensitivity in esophageal cancer patients.
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