Capsaicin and resveratrol are strong chemopreventive agents with promising human consumption safety records and anticarcinogenic activities. However, the mechanism by which they induce apoptosis in tumor cells remains to be defined. In this study, we examined the role of nitric oxide (NO•) during apoptosis induced by these agents in A375 human melanoma cells. Capsaicin and resveratrol, alone or in combination, inhibited cell growth and promoted apoptosis by the elevation of NO• in A375 cells. Increased NO• production following treatment stimulated p53 and triggered mitochondrial apoptotic events by inducing conformational changes in Bax and Bcl-2 with subsequent release of cytochrome c and activation of caspase 9 and 3. Caspase 8 activation concurrently appeared to be mediated by death receptor processing and downstream caspases. Collectively, our data suggest that capsaicin and resveratrol activate the mitochondrial and death receptor pathways, working together to induce apoptosis in A375 cells, and indicate that NO• could be considered a potential target for improvement of the effectiveness of melanoma treatment.

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