Biological targets, like ERα in hormone-dependant cancer therapies, are the focus of many cancer research groups. We have previously reported the synthesis of a new 17β-estradiol-linked platinum(II) hybrid (E2-Pt(II)), VP-128, that binds to ERα with high affinity. This drug has also demonstrated high biological activity towards breast (MCF-7, ZR-75-1, MDA-MB-468, MDA-MB-231 and HS578-T) and ovarian (OVCAR-3, SKOV-3, A2780, and A2780-CP) cancer cells, in vitro and in vivo using ERα positive or negative cells. MTT assays revealed that VP-128 decreased more efficiently the viability of breast and ovarian cancer cells than cisplatin itself in vitro. Moreover, the expression of ERα sensitized the cells to the growth-suppressive effect of VP-128. Hoechst nuclear staining revealed an improved efficiency of VP-128 compared to cisplatin to induce apoptosis of breast cancer cells, which was enhanced in ERα-positive cells. Western blot analysis revealed that VP-128 induced more caspase-9 fragments, but less caspase-3 and PARP fragments in breast cancer cells compared to cisplatin, suggesting that the two drugs have a different mode of action. Nonetheless, VP-128 and cisplatin similarly decreased the levels of XIAP and phosphorylated/active Akt in sensitive cells. RT-PCR analysis showed that ERα is expressed and activated in response to E2 and VP-128 in MCF-7 cells, as indicated by an increase of pS2 and c-myc transcripts. Although exposure to E2 induced TGF-β3 expression in both ERα+/ERβ+ MCF-7 cells and ERα-/ERβ+ MDA-MB-468 cells, VP-128 induced TGF-β3 expression only in MCF-7 cells. This suggests that VP-128 induces TGF-β3 expression in an ERα-dependent mechanism. In agreement, western blot analysis showed that at each dose tested, VP-128 treatment rapidly induced the translocation of ERα to the nucleus in MCF-7 cells, similar to E2 treatment, whereas ERβ was imported to the nucleus in response to E2 but not to VP-128. The activation of caspase-independent apoptosis was observed in MDA-MB-468 cells, where VP-128 rapidly induced the translocation of AIF to the nucleus, as revealed by western blot analysis of cytosolic and nuclear cell extracts. AIF subcellular localization was not modified by VP-128 in MCF-7 cells. Finally, using human breast and ovarian cancer cell xenografts in nude mice, we found that VP-128 had improved antitumour activity compared to cisplatin in vivo, and was more specific and selective towards hormone-dependent cancer cells. Altogether these results highlight the therapeutic value of this unique E2-Pt(II) hybrid for the treatment of hormone-dependent breast cancers, and provide preliminary proof-of-concept for efficient targeting of ERα by E2-cisplatin hybrids.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4467.