Resveratrol Induces Cell-Cycle Disruption and Apoptosis in Chemoresistant B16 Melanoma

Resveratrol, a naturally occurring polyphenol, has been shown to possess chemopreventive activities. In this study, we show that resveratrol (0-500 mu M) inhibits the growth of a doxorubicin-resistant B16 melanoma cell subtitle (B16/DOX) (IC50 = 25 mu M after 72 h, P < 0.05). This was accomplished by imposing an artificial checkpoint at the G(1)-S phase transition, as demonstrated by cell-cycle analysis and down-regulation of cyclin D1/cdk4 anti increased of p53 expression level. The G(1)-phase arrest of cell cycle in resveratrol-treated (10-100 mu M) B16/DOX cells was followed by the induction of apoptosis, which was revealed by pyknotic nuclei and fragmented DNA. Resveratrol also potentiated at subtoxic dose (25 mu M for 24 h) doxorubicin cytotoxicity in the chemoresistant B16 melanoma (P<0.01). When administered to mice, resveratrol (12.5 mg/kg) reduced the growth of an established B16/DOX melanoma and prolonged survival (32% compared to untreated mice). All these data support a potential use of resveratrol alone or in combination with other chemotherapeutic agents in the management of chemoresistant tumors. J. Cell. Biochem. 110: 893-902, 2010. (C) 2010 Wiley-Liss. Inc.