Effects and mechanisms of proton pump inhibitors as a novel chemosensitizer on human gastric adenocarcinoma (SGC7901) cells

Upregulation of proton extrusion is critical for tumor cell survival in an ischemic microenvironment with a lower extracellular pH (pHe). Lower pHe and higher intracellular pH (pHi) benefit cancer cells for invasion and growth. Vacuolar H⁺-ATPases (V-H⁺-ATPases) play a critical role in regulating the transmembrane pH gradient. Proton Pump Inhibitors (PPI), mainly treating acid-related diseases, could inhibit the expression of V-H⁺-ATPases. We have investigated whether PPI decreases the pHi of the human gastric adenocarcinoma cell line, SGC7901, by inhibiting V-H⁺-ATPases so as to enhance the cytotoxicity of anti-tumor drugs. We have assessed the optimal treatment time, pretreatment dosage of PPI and the possible mechanism of action. PPI exceeding 10 μg/ml inhibited protein expression of V-H⁺-ATPases in a dose-dependent manner, decreased the pHi value and reversed the transmembrane pH gradient, whereas PPI at final concentration of 1 μg/ml could not. Changes of the pH gradient were positively correlated with PPI concentration. The inhibitory effects of PPI on V-H⁺-ATPases primarily occurs from 12 h to 24 h after PPI pretreatment (P < 0.05). The pHi value of SGC7901 was lowest 24 h after PPI pretreatment (P < 0.05). Administration of anti-tumor drugs 24 h after PPI pretreatment produced the most cytotoxic effects on SGC7901 (P < 0.05) and significantly improved the early and total apoptosis rates (P < 0.01). PPI exceeding 20 μg/ml also significantly reduced the ADR-releasing index, thereby enhancing the intracellular ADR concentration (P < 0.01). Therefore, PPI could enhance the cytotoxic effects of anti-tumor drugs on the SGC7901 cells.