Journal
ANTI-CANCER DRUGS
Volume 21, Issue 5, Pages 494-501Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CAD.0b013e328336e927
Keywords
A375 cells; apoptosis; melanoma; oxymatrine; reactive oxygen species
Categories
Funding
- Natural Science Foundation of Shanghai [08JC1407100, 09ZR1410000]
- Program for Outstanding Medical Academic Leader of Shanghai
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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. Anti-Cancer Drugs 21:494-501 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
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