Anti-Melanoma Effects of Vorinostat in Combination with Polyphenolic Antioxidant (−)-Epigallocatechin-3-Gallate (EGCG)

Abstract

Melanoma is an aggressive neoplasm with a propensity for metastases and resistance to therapy. Previously, we showed that (-)-epigallocatechin-3-gallate (EGCG), the major polyphenolic antioxidant present in green tea, resulted in a significant decrease in the viability and growth of melanoma and induction of apoptosis via modulation of the cki-cdk-cyclin network and Bcl2 family proteins. Epigenetic regulation of gene transcription by histone deacetylase (HDAC) inhibitors is gaining momentum as a novel cancer therapy. SAHA-suberoylanilidine hydroxamic acid Zolinza (vorinostat) is the first HDAC inhibitor approved by the U.S. FDA. In this study, we determined if vorinostat alone or in combination with EGCG imparts anti-proliferative effects against human melanoma cells. Employing human melanoma cell lines A-375, Hs-294T and G-361, we determined the effect of vorinostat and/or EGCG on 1) growth/viability and colony formation, 2) apoptosis, and 3) the critical molecules involved in cell cycle and apoptosis regulation. Our data demonstrated that the anti-proliferative effects of vorinostat were greater than or similar to those of EGCG among the cell lines tested. Furthermore, relative to monotherapy, the combination treatment resulted in significantly greater inhibition of cell proliferation, increased apoptosis, activation of p21, p27 and caspases (3, 7 and 9) and Bax as well as down-regulation of cdk2, cdk4, cyclin A, NF-kappaB protein p65/RelA and Bcl2 protein and transcript. Our preclinical findings suggest that combination therapy with EGCG and vorinostat may be beneficial for the management of human melanoma.