The resveratrol analogue 4,4'-dihydroxy-trans-stilbene suppresses transformation in normal mouse fibroblasts and inhibits proliferation and invasion of human breast cancer cells.

4,4’-dihydroxy-trans-stilbene is a synthetic analogue of resveratrol, a phytoalexin known for its biological activities. We previously demonstrated that 4,4’-dihydroxy-trans-stilbene exerts an antiproliferative effect on normal human fibroblasts that is higher than that of the natural parent molecule. No evidence regarding its role in human cancer cell lines has been found so far. Here, we investigated the effects of 4,4’-dihydroxy-trans-stilbene both on chemicalinduced transformation of BALB/c 3T3 mouse fibroblasts and on the proliferation and invasion of human breast cancer MCF-7 cells. The results showed that 4,4’-dihydroxy-transstilbene markedly suppresses the two-stage (3-methylcholanthrene plus 12-Otetradecanoylphorbol- 13-acetate) cell transformation. Compared with resveratrol, 4,4’- dihydroxy-trans-stilbene inhibited both anchorage-dependent and -independent MCF-7 growth more efficiently. In addition, a reduction in the number of cells in S-phase, characterised by a concomitant increase in the levels of p21 and p53 proteins, together with a strong inhibition of pRb protein phosphorylation, was observed in 4,4’-dihydroxy-transstilbene- treated cells. Furthermore, 4,4’-dihydroxy-trans-stilbene effected a strong reduction in matrix metalloproteinase-2 and -9 activities, concomitantly with a marked inhibition of cell adhesion to the extracellular matrix components as well as inhibition of cell migration and invasion. Importantly, modulation of the adhesion molecule E-cadherin was also found in 4,4’-dihydroxy-trans-stilbene-treated cells. Taken together, these results demonstrate that the two 4,4’-hydroxyl groups on the stilbenic backbone make 4,4’-dihydroxy-trans-stilbene a more active molecule than resveratrol in inhibiting neoplastic transformation, cancer cell proliferation and invasion. In conclusion, this study suggests that 4,4’-dihydroxy-transstilbene could be a promising anti-cancer agent.