PPI pretreatment was associated with the inhibition of V-H + -ATPase activity and increases in both extracellular pH and the pH of lysosomal organelles. Results: PPI pretreatment sensitized tumor cell lines to the effects of cisplatin, 5-fluorouracil, and vinblastine, with an IC 50 value reduction up to 2 logs. Finally, we evaluated human melanoma growth and cisplatin sensitivity with or without omeprazole pretreatment in xenografted SCID/SCID mice. 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. 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 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. Some mechanisms of tumor resistance to cytotoxic drugs may involve increased acidification of extracellular compartments. Background: Resistance to antitumor agents is a major cause of treatment failure in patients with cancer.
0 kommentar(er)
