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

作者：Qian, Xia; Li, Jing; Ding, Jianhua; Wang, Zhiyuan; Duan, Lei; Hu, Gang^*

来源：Biochemical Pharmacology, 2008, 76(12): 1705-1715.

DOI：10.1016/j.bcp.2008.09.009

• Glibenclamide
• Human gastric cancer cell line
• MGC-803
• Reactive oxygen species
• C-jun NH(2)-terminal kinase
• Akt

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.

• 出版日期2008-12-15
• 单位南京医科大学