Trans- and cis-stilbene polyphenols induced rapid perinuclear mitochondrial clustering and p53-independent apoptosis in cancer cells but not normal cells

We previously reported that 3,4,5,4′-tetramethoxy-trans-stilbene (MR-4) induces p53 and perinuclear mitochondrial clustering in cancer cells [Gosslau, A., Chen, M., Ho, C.-T., Chen, K.Y., 2005, A methoxy derivative of resveratrol analogue selectively induced activation of the mitochondrial apoptotic pathway in transformed fibroblasts. Br. J. Cancer 92, 513-521.]. Here we extended the study to over 20 trans-stilbene derivatives and their cis-isomers to explore structure activity relationship. Among them, 3,4,5,4′-tetramethoxy-cis-stilbene (MC-4), the cis-isomer of MR-4, was most potent, with IC50 of 20 nM for growth inhibition. MC-4 induced a rapid perinuclear mitochondrial clustering, membrane permeability transition, cytochrome c release and DNA fragmentation. To determine whether trans- and cis-stilbene polyphenols may share a common mechanism, we compared the effects of MC-4 and MR-4 in three isogenic cell lines derived from the colorectal carcinoma HCT116 cells: p53+/+ (p53-wt), p53−/− (p53-null) and p21−/− (p21-null). Deletion of either p53 or p21 neither blocked the effects of MC-4 or MR-4 on mitochondrial clustering nor inhibited apoptosis, indicating that the actions of both stilbenes are independent of p53 and p21. Although microtubule disruption has been proposed to account for the action of some cis-stilbene polyphenols, we did not observe differences in microtubule dynamics between cells treated with MC-4 and MR-4. These findings suggest that MC-4 and MR-4 may share a common mechanism whereby the perinucear mitochondrial clustering, rather than p53, p21, or microtubule depolymerization, is critical for their pro-apoptotic action.