The effect of the naturally occurring
polyphenol resveratrol (3,5,4'-trihydroxy-trans-
stilbene; RES) on growth, cell cycle, and
cyclins A, E, and B1 expression was investigated in the human SK-Mel-28
melanoma cell line. In addition, the structurally related compounds
4-hydroxy-trans-stilbene (4HST),
piceatannol (3,5,3',4'-tetrahydroxy-trans-
stilbene (PICE), and 4-trans-stilbenemethanol (4STMe) were also assayed in order to investigate the requirements of
stilbenes to exert activity against
melanoma cells. Both RES and 4HST inhibited cell growth in a dose- and time-dependent manner and upregulated the expression of
cyclins A, E, and B1 with subsequent irreversible arrest of
melanoma cells in the S-phase, concomitant with a decrease in G0/G1 and G2/M phases. In addition, potent apoptosis-mediated cell death was detected with the
annexin V assay whereas no apoptosis was observed by flow cytometry, which encourages the assay of different methodologies to evaluate the effect of
polyphenols on cell lines. The effect of PICE was not evaluated because of its instability in the reaction medium. No effect on cell cycle and
cyclins expression was observed when 4STMe was assayed, which supported the critical requirement of the 4'-hydroxystyryl moiety to exert the above effects. In addition, this structural requirement also influenced the cellular uptake of
stilbenes. The presence of two extra
hydroxyl groups in RES increased its cytotoxicity whereas it diminished its efficiency to inhibit cell growth, upregulate
cyclins expression, and arrest cell cycle in the S-phase with respect to 4HST. The present study suggests that the antimelanoma properties of dietary
stilbenes, such as grape RES, cannot be ruled out, taking into account previous studies concerning the relationship between plasma and tissue concentrations and pharmacological activity of RES in animal models.