Glibenclamide exerts an antitumor activity through reactive oxygen species-c-jun NH2-terminal kinase pathway in human gastric cancer cell line MGC-803.
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 (O2-) 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 NH2-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.
Qian
Xia
X
Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, PR China.
Li
Jing
J
Ding
Jianhua
J
Wang
Zhiyuan
Z
Duan
Lei
L
Hu
Gang
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005905:Glyburide / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013274:Stomach Neoplasms
D000970:Antineoplastic Agents; D026902:Potassium Channel Blockers; D017382:Reactive Oxygen Species; D048031:JNK Mitogen-Activated Protein Kinases; D005905:Glyburide