The role of endogenous reactive oxygen species in oxymatrine-induced caspase-3-dependent apoptosis in human melanoma A375 cells.
Rapid increases in incidence and mortality of human malignant melanoma are observed worldwide; thus, the development of new effective chemicals to control melanoma is urgent. In this study, the cytotoxic effect of oxymatrine, a natural quinolizidine alkaloid, against three human melanoma cell lines (A375, Sk-Mel-28, MM96L) and the underlying mechanisms were investigated. Oxymatrine killed all three human melanoma cell lines in a dose-dependent manner. The compound also dose-dependently caused apoptosis in human melanoma A375 cells. In addition, oxymatrine induced a remarkable change in mitochondrial membrane potential and triggered the release of cytochrome c from mitochondria to cytosol. Furthermore, this small compound resulted in a marked activation of capase-3, caspase-9, and poly (ADP-ribose) polymerase, while caspase-3 inhibitor Z-DEVD-FMK significantly reversed the proapoptotic effect of oxymatrine in A375 cells. Moreover, oxymatrine also dose-dependently increased the generation of reactive oxygen species in A375 cells, and N-acetylcysteine, a reactive oxygen species production inhibitor, almost completely blocked oxymatrine-induced apoptosis. In conclusion, our findings suggest that oxymatrine triggers oxidative stress, resulting in the collapse of the mitochondrial transmembrane potential, which in turn leads to cytochrome c release and apoptosis through the intrinsic caspase-9/caspase-3 pathway in human melanoma A375 cells.
Zhang
Yingfan
Y
Department of Plastic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Liu
Huanhai
H
Jin
Jiyang
J
Zhu
Xiaohai
X
Lu
Lixuan
L
Jiang
Hua
H
D000111:Acetylcysteine / Q000378:metabolism; D000470:Alkaloids / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D018384:Oxidative Stress; D011807:Quinolizines / Q000494:pharmacology / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000093842:Matrines
D000111:Acetylcysteine; D000470:Alkaloids; D000970:Antineoplastic Agents; D053148:Caspase 3; D011807:Quinolizines; D017382:Reactive Oxygen Species; C037573:oxymatrine; D000093842:Matrines