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 microg/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 microg/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 12h to 24h after PPI pretreatment (P<0.05). The pHi value of SGC7901 was lowest 24h after PPI pretreatment (P<0.05). Administration of anti-tumor drugs 24h 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 microg/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.
Chen
Min
M
Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.
Zou
Xiaoping
X
Luo
Hesheng
H
Cao
Jun
J
Zhang
Xiaoqi
X
Zhang
Bin
B
Liu
Wenjia
W
D000230:Adenocarcinoma / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000970:Antineoplastic Agents; D054328:Proton Pump Inhibitors; D004317:Doxorubicin; D000251:Adenosine Triphosphatases