Glibenclamide exerts an antitumor activity through reactive oxygen species–c-jun NH(2)-terminal kinase pathway in human gastric cancer cell line MGC-803

Abstract

Glibenclamide, a blocker of ATP-sensitive potassium (K ATP) channels, can suppress progression of many cancers, but the involved mechanism is unclear. Herein we reported that MGC-803 cells expressed the K ATP channels composed of Kir6.2 and SUR1 subunits. Glibenclamide induced cellular viability decline, coupled with cell apoptosis and reactive oxygen species (ROS) generation in MGC-803 cells. Meanwhile, glibenclamide increased NADPH oxidase catalytic subunit gp91 phox expression and superoxide anion (O 2 −) generation, and caused mitochondrial respiration dysfunction in MGC-803 cells, suggesting that glibenclamide induced an increase of ROS derived from NADPH oxidase and mitochondria. Glibenclamide could also lead to loss of mitochondrial membrane potential, release of cytochrome c and apoptosis-inducing factor (AIF), and activation of c-jun NH(2)-terminal kinase (JNK) in MGC-803 cells. Pretreatment with antioxidant N-acetyl- l-cysteine (NAC) prevented glibenclamide-induced JNK activation, apoptosis and cellular viability decline. Furthermore, glibenclamide greatly decreased the cellular viability, induced apoptosis and inhibited Akt activation in wild-type mouse embryonic fibroblast (MEF) cells but not in JNK1 −/− or JNK2 −/− MEF cells. Taken together, our study reveals that glibenclamide exerts an antitumor activity in MGC-803 cells by activating ROS-dependent, JNK-driven cell apoptosis. These findings provide insights into the use of glibenclamide in the treatment of human gastric cancer.