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Introduction: V-ATPase is highly expressed in cancer cells and has been shown to be involved in the transformation of normal cells into cancer cells, invasion of tissues, survival of cancer cells, and the formation of drug resistance. The use of proton pump inhibitors (PPIs) as V-ATPase inhibitors has been shown to enhance the efficacy of chemotherapy in some cancers. Material and Method: We investigated the effect of proton pump inhibitors on esophageal squamous cell carcinoma, one of the major causes of cancer mortality in Japan. First, three PPIs at various concentrations (lansoprazole, esomeprazole, and bonoprazan) and pyrimidine fluoride (5-FU), a key drug in chemotherapy for esophageal cancer, were used as basic medical agents. Human esophageal squamous cell lines, KYSE50 and KYSE70, were prepared and treated with the above drugs, and cell viability assays were performed using Cell Counting Kit 8 for 72 hours. We then performed a retrospective clinical study of 40 patients with clinical stage IV esophageal squamous cell carcinoma treated with the drugs at Kyoto Prefectural University of Medicine Hospital in Japan. Result: In cell survival assays, PPIs showed significantly enhanced cytotoxic effects of pyrimidine fluoride on all cell lines compared with those not treated with PPIs. Clinical data showed no difference in the incidence of treatment-related adverse events between the PPI and non-PPI groups. The response rate after two courses of chemotherapy was 66.7% in the PPI group and 40.9% in the non-PPI group (p=0.102). Kaplan-Meier analysis showed improved OS in patients treated with PPIs (log rank test p=0.032), and multivariate analysis showed that PPI use was associated with a more favorable OS (p=0.009,HR 0.33,95% CI 0.12-0.76 ). Conclusion: In the chemotherapy of esophageal squamous cell carcinoma, the use of PPIs may enhance the cytotoxic effect of the key drug, pyrimidine fluoride, while ensuring safety, and may lead to better therapeutic efficacy. Citation Format: Ryuichi Morita, Takeshi Ishikawa, Shinya Matsumura, Tomoki Sakakida, Juichiro Yoshida, Toshifumi Doi, Ryohei Hirose, Ken Inoue, Osamu Dohi, Naohisa Yoshida, Kazuhiko Uchiyama, Tomohisa Takagi, Hideyuki Konishi, Yuji Naito, Yoshito Itoh. Proton pump inhibitors as a potential combination therapy with existing chemotherapy for esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1688. |
