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Cell Biology International (2009) 33, 1008–1019 (Printed in Great Britain)

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

Min Chen^a1, Xiaoping Zou^b*1, Hesheng Luo^a**, Jun Cao^b, Xiaoqi Zhang^b, Bin Zhang^b and Wenjia Liu^b

^aDepartment of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China
^bDepartment of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing 210008, PR China

Abstract

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 10μg/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 1μg/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 20μg/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.

Key words: Vacuolar H⁺-ATPases, Tumor acidity, Proton pump inhibitors, Transmembrane pH gradient.

¹Min Chen and Xiaoping Zou contributed equally to this work.

^*Corresponding author. Tel.: +86 25 88304616 20601; fax: +86 25 83105206.

^**Corresponding author. Tel.: +86 13618644197; fax: +86 27 88042292.

Received 28 December 2008/9 April 2009; accepted 7 May 2009