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Grape Polyphenol Resveratrol and the Related Molecule 4-Hydroxystilbene Induce Growth Inhibition, Apoptosis, S-Phase Arrest, and Upregulation of Cyclins A, E, and B1 in Human SK-Mel-28 Melanoma Cells

AuthorsLarrosa, Mar ; Tomás Barberán, Francisco ; Espín de Gea, Juan Carlos
Grape polyphenol
Cell cycle
Flow cytometry
Issue Date4-Jul-2003
PublisherAmerican Chemical Society
CitationJournal of Agricultural and Food Chemistry 51(16): 4576-4584 (2003)
AbstractThe 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.
Description9 pages, 7 figures, 1 table.-- Results was presented at the 18th European Workshop on Drug Metabolism, September 2002, Valencia, Spain.
Publisher version (URL)http://dx.doi.org/10.1021/jf030073c
Appears in Collections:(CEBAS) Artículos
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