Effect of Proton Pump Inhibitor Pretreatment on Resistance of Solid Tumors to Cytotoxic Drugs

作者：Francesca Luciani, Massimo Spada, Angelo De Milito, Agnese Molinari, Licia Rivoltini, Annalisa Montinaro, Manuela Marra, Luana Lugini, Mariantonia Logozzi, Francesco Lozupone, Cristina Federici, Elisabetta Iessi, Giorgio Parmiani, Giuseppe Arancia, Filippo Belardelli, Stefano Fais · 发表于：JNCI Journal of the National Cancer Institute · 年份：2004 · DOI：10.1093/jnci/djh305 · 被引用次数：441 · 研究领域：ATP Synthase and ATPases Research、Cancer, Hypoxia, and Metabolism、Ion Transport and Channel Regulation

BACKGROUND: Resistance to antitumor agents is a major cause of treatment failure in patients with cancer. Some mechanisms of tumor resistance to cytotoxic drugs may involve increased acidification of extracellular compartments. We investigated whether proton pump inhibitors (PPIs), currently used in the anti-acid treatment of peptic disease, could inhibit the acidification of the tumor microenvironment and increase the sensitivity of tumor cells to cytotoxic agents. METHODS: We pretreated cell lines derived from human melanomas, adenocarcinomas, and lymphomas with the PPIs omeprazole, esomeprazole, or pantoprazole and tested their response to cytotoxic drugs in cell death assays. We also evaluated extracellular and intracellular pH and vacuolar-H+-ATPase (V-H+-ATPase) expression, distribution, and activity in PPI-pretreated cells by using western blot analyses, immunocytochemistry, laser scanning confocal analysis, and bioluminescence assays. Finally, we evaluated human melanoma growth and cisplatin sensitivity with or without omeprazole pretreatment in xenografted SCID/SCID mice. RESULTS: PPI pretreatment sensitized tumor cell lines to the effects of cisplatin, 5-fluorouracil, and vinblastine, with an IC50 value reduction up to 2 logs. PPI pretreatment was associated with the inhibition of V-H+-ATPase activity and increases in both extracellular pH and the pH of lysosomal organelles. PPI pretreatment induced a marked increase in the cytoplasmic retention of the cytotoxic dru...