Selective Induction of Apoptosis with Proton Pump Inhibitor in Gastric Cancer Cells

Abstract

To survive in an ischemic microenvironment with a lower extracellular pH, ability to up-regulate proton extrusion is critical for cancer cell survival. Gastric H+/K(+)-ATPase exchanges luminal K+ for cytoplasmic H+ and is the enzyme primarily responsible for gastric acidification. On the basis of the fact that blocking the clearance of acidic metabolites are known to induce the cell death, we hypothesized that pantoprazole (PPZ), one of gastric H+/K(+)-ATPase inhibitors used frequently to treat acid-related diseases, could inhibit growth of tumor cells. Genomic DNA fragmentation, terminal deoxynucleotidyl transferase (Tdt)-mediated nick end labeling assay, and annexin V staining were performed to detect PPZ-induced apoptosis. Mitogen-activated protein kinase activation and heat shock proteins expression were determined by immunoblot with specific antibodies. The antitumor effect of PPZ was evaluated in vivo by a xenograft model of nude mice. After PPZ treatment, apoptotic cell death was seen selectively in cancer cells and was accompanied with extracellular signal-regulated kinase deactivation. By contrast, normal gastric mucosal cells showed the resistance to PPZ-induced apoptosis through the overexpression of antiapoptotic regulators including HSP70 and HSP27. In a xenograft model of nude mice, administration of PPZ significantly inhibited tumorigenesis and induced large-scale apoptosis of tumor cells. PPZ selectively induced in vivo and in vitro apoptotic cell death in gastric cancer, suggesting that proton pump inhibitors could be used for selective anticancer effects.