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1. J Cell Biochem. 2012 Mar 6. doi: 10.1002/jcb.24122. [Epub ahead of print]

Reversal effects of pantoprazole on multidrug resistance in human gastric
adenocarcinoma cells by down-regulating the V-ATPases/mTOR/HIF-1α/P-gp and MRP1
signaling pathway in vitro and in vivo.

Chen M, Huang SL, Zhang XQ, Zhang B, Zhu H, Yang VW, Zou XP.

Department of Gastroenterology, the affiliated Drum Tower Hospital of Nanjing
University, Medical School, Nanjing 210008, P.R. China.

BACKGROUND AND AIMS: To investigate reversal effects of Pantoprazole (PPZ) on
multidrug resistance (MDR) in human gastric adenocarcinoma cells in vivo and in
vitro. METHODS: Human gastric adenocarcinoma cell SGC7901 was cultured in
RPMI-1640 medium supplemented with 10% fetal bovine serum and antibiotics in a
humidified 5% CO(2) atmosphere at 37 °C. Adriamycin (ADR)-resistant cells were
cultured with addition of 0.8 µg/ml of ADR maintaining MDR phenotype. ADR was
used to calculate ADR releasing index; CCK-8 Assay was performed to evaluate the
cytotoxicity of anti-tumor drugs; BCECF-AM pH-sensitive fluorescent probe was
used to measure intracellular pH (pHi) value of cells, whereas pH value of medium
was considered as extracellular pH (pHe) value; Western blotting and
immunofluorescent staining analyses were employed to determine protein
expressions and intracellular distributions of Vacuolar H(+) -ATPases
(V-ATPases), mTOR, HIF-1α, P-glycoprotein (P-gp) and multidrug resistant protein
1 (MRP1); SGC7901 and SGC7901/ADR cells were inoculated in athymic nude mice.
Thereafter, effects of ADR with or without PPZ pretreatment were compared by
determining the tumor size and weight, apoptotic cells in tumor tissues were
detected by TUNEL assay. RESULTS: At concentrations greater than 20 µg/ml, PPZ
pretreatment reduced ADR releasing index and significantly enhanced intracellular
ADR concentration of SGC7901 (P < 0.01). Similarly, PPZ pretreatment
significantly decreased ADR releasing index of SGC7901/ADR dose-dependently
(P < 0.01). PPZ pretreatment also decreased cell viabilities of SGG7901 and
SGC7901/ADR dose-dependently. After 24-hr PPZ pretreatment, administration of
chemotherapeutic agents demonstrated maximal cytotoxic effects on SGC7901 and
SGC7901/ADR cells (P < 0.05). The resistance index in PPZ pretreatment group was
significantly lower than that in non-PPZ pretreatment group (3.71 vs. 14.80). PPZ
at concentration greater than 10 µg/ml significantly decreased pHi in SGC7901 and
SGC7901/ADR cells and diminished or reversed transmembrane pH gradient
(P < 0.05). PPZ pretreatment also significantly inhibited protein expressions of
V-ATPases, mTOR, HIF-1α, P-gp and MRP1, and alter intracellular expressions in
parent and ADR-resistant cells (P < 0.05). In vivo experiments further confirmed
that PPZ pretreatment could enhance antitumor effects of ADR on xenografted tumor
of nude mice and also improve the apoptotic index in xenografted tumor tissues.
CONCLUUSIONS: PPZ pretreatment enhances the cytotoxic effects of anti-tumor drugs
on SGC7901 and reverse MDR of SGC7901/ADR by downregulating the
V-ATPases/mTOR/HIF-1α/P-gp and MRP1 signaling pathway. J. Cell. Biochem. © 2012
Wiley Periodicals, Inc.

Copyright © 2012 Wiley Periodicals, Inc.

PMID: 22396185 [PubMed - as supplied by publisher]