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Anticancer effects of the metabolic products of the resveratrol analogue, DMU212: Structural requirements for potency

Anticancer effects of the metabolic products of the resveratrol analogue, DMU212: Structural requirements for potency,10.1016/j.ejmech.2011.03.049,Eur

Anticancer effects of the metabolic products of the resveratrol analogue, DMU212: Structural requirements for potency  
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The methoxylated trans-stilbene resveratrol analogue, (E)-3,4,5,4′-tetramethoxystilbene (1), has shown promising antiproliferative activity in in vitro cell line and in vivo models. In vivo1 gives rise to several metabolic products through demethylation or hydroxylation reactions at the stilbene moiety. In the present study we examined the anticancer activity of 1 and the metabolites (E)-3′-hydroxy-3,4,5,4′-tetramethoxystilbene (2), (E)-4′-hydroxy-3,4,5-trimethoxystilbene (3), (E)-4-hydroxy-3,5,4′-trimethoxystilbene (4) and (E)-3-hydroxy-4,5,4′-trimethoxystilbene (5) by means of cell viability testing, cell cycle analysis, immunostaining and Western blotting. Compounds 1 and 2 exhibited submicromolar toxicity in MCF-7 breast adenocarcinoma and HepG2 hepatoma cells, whereas 3, 4 and 5 were inactive in terms of inhibition of cellular proliferation. Incubation with 1 or 2 at 10μM for 24h induced apoptosis and G2/M cell cycle arrest in MCF-7 and HepG2 cells. Immunostaining of MCF-7 cells for β-tubulin in the presence of either 1 or 2 revealed shorter localization of the protein around the nucleus, as compared to control cells. Western blot analyses further demonstrated that treatment with either 1 or 2 at concentrations between 30 and 50μM for 24h caused a downregulation in the levels of β-tubulin and cyclin D1 expression and an upregulation in the levels of p53 expression in MCF-7 and HepG2 cells. 2 further increased the ratio of mRNA levels of the apoptosis-related genes Bax/Bcl-xL in both MCF-7 and HepG2 cells in a dose-dependent manner. We conclude that 2 inhibits HepG2 and MCF-7 cellular proliferation by inducing apoptosis and G2/M arrest through p53 and Bax/Bcl-xL upregulation. Our findings further demonstrate that trimethoxy substitutions along with the presence of a methoxy group at position 4′ are necessary for retaining the activity of 1.
Journal: European Journal of Medicinal Chemistry - EUR J MED CHEM , vol. 46, no. 6, pp. 2586-2595, 2011
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