Previous studies revealed that polydatin, a natural small compound, possessed protective effect against ischemia/reperfusion injury and inflammation. However, the action and molecular mechanism of its potent anti-cancer activity remain poorly understood. In the present study, polydatin significantly killed several human tumor cell lines in a dose- and time-dependent manner. The compound also dose-dependently caused mitochondrial apoptosis in human nasopharyngeal carcinoma CNE cells. In addition, polydatin triggered endoplasmic reticulum (ER) stress and down-regulated the phosphorylation of Akt in CNE cells, while knock-down of CCAAT/enhancer-binding protein homologous protein (CHOP) dramatically abrogated the inactivation of Akt and reversed the pro-apoptotic effect of polydatin. Furthermore, polydatin provoked the generation of reactive oxygen species in CNE cells, while the antioxidant N-acetyl cysteine almost completely blocked the activation of ER stress and apoptosis, suggesting polydatin-induced reactive oxygen species is an early event that triggers ER stress mitochondrial apoptotic pathways in CNE cells. Taken together, these findings strongly suggest that polydatin might be a promising anti-tumor drug and our data provide the molecular theoretical basis for clinical application of polydatin.

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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.