The resveratrol analogue 4,4'-dihydroxy-trans-stilbene inhibits cell proliferation with higher efficiency but different mechanism from resveratrol.
Int J Biochem Cell Biol
; 41(12): 2493-502, 2009 Dec.
Article
em En
| MEDLINE
| ID: mdl-19679195
ABSTRACT
Resveratrol (3,4',5-trihydroxy-trans-stilbene) is a natural phytoalexin found in grapes and wine, which shows antiproliferative activity. We previously found that 4-hydroxy group in the trans conformation was absolutely required for the inhibition of cell proliferation. In the present work we have synthesized the resveratrol analogue 4,4'-dihydroxy-trans-stilbene, which contains two OH in 4' and 4 positions, with the aim of developing a compound with an antiproliferative potential higher than that of resveratrol, on the basis of the correlation between structure and activity previously observed. In comparison with resveratrol, 4,4'-dihydroxy-trans-stilbene inhibited cell clonogenic efficiency of fibroblasts nine times more although with a different mechanism. First, 4,4'-dihydroxy-trans-stilbene induced predominantly an accumulation of cells in G1 phase, whereas resveratrol perturbed the G1/S phase transition. Second, although both compounds were able to inhibit DNA polymerase (pol) delta in an in vitro assay, 4, 4'-dihydroxy-trans-stilbene did not affect pol alpha activity. Finally, 4,4'-dihydroxy-trans-stilbene increased p21(CDKN1A) and p53 protein levels, whereas resveratrol led to phosphorylation of the S-phase checkpoint protein Chk1. Taken together, our results demonstrated for the first time that the two hydroxyl groups on 4- and 4'- positions of the stilbenic backbone enhance the antiproliferative effect and introduce additional targets in the mechanism of action of resveratrol. In conclusion, 4,4'-dihydroxy-trans-stilbene has potent antiproliferative activities that differ from the effect of resveratrol shown in this system, suggesting that it warrants further development as a potential chemopreventive or therapeutic agent.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Estilbenos
/
Proteínas de Ciclo Celular
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DNA Polimerase III
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Fibroblastos
Limite:
Humans
Idioma:
En
Revista:
Int J Biochem Cell Biol
Assunto da revista:
BIOQUIMICA
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Itália
País de publicação:
HOLANDA
/
HOLLAND
/
NETHERLANDS
/
NL
/
PAISES BAJOS
/
THE NETHERLANDS