Since several cancers in women are estrogen-dependent due to the presence and overexpression of estrogen receptor (ER), we sought to determine the possibility to use it as a target for chemotherapy and have designed unique molecules capable of doing so. We have recently reported the synthesis of a new family of E2-platinum(II) hybrids. Earlier studies revealed VP-128 hybrid to show high efficiency compared to cisplatin towards breast cancer cells. VP-128 was also selective towards ER+ breast cancer xenografts in nude mice. In the present study, we have investigated, in vitro and in vivo, the antitumor activity of VP-128 using ovarian cancer cell (Ovcar-3, Skov-3, A2780 and A2780CP) and investigated the mode of action of this new hybrid against this type of cancer. We have also developed a new model of study by transfecting A2780 cells with ERα gene to better compare our hybrids with cells having the same genotype excepted for the presence or absence of ERα. MTT assays revealed that VP-128 decreased more efficiently the viability of 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 ovarian cancer cells. Western blot analysis revealed that VP-128 induced more caspase-9, caspase-3 and PARP fragments in ovarian cancer cells compared to cisplatin, suggesting that VP-128 is more effective to kill cancer cells. VP-128 decreased the levels of XIAP and phosphorylated/active Akt more than cisplatin in ovarian cancer cells again suggesting that VP-128 has higher biological activity. The activation of caspase-independent apoptosis was observed in A2780 ER- cells, where VP-128 rapidly induced the translocation of AIF to the nucleus, as revealed by Western blot analysis of cytosolic/nuclear cell extracts and immunofluorescence microscopy. Converely, AIF subcellular localization was not modified by VP-128 in Ovcar-3 ER+ cells. Finally, using 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 ER+ than ER- xenografts. Using newly A2780 ERα+ transfected cells, we observed a significant efficiency of the VP-128 hybrid to induce apoptosis compared to A2780 ERα- which further indicate specificity toward the receptor. Altogether these results highlight the therapeutic value of VP-128 for the treatment of hormone-dependent ovarian cancers, and provide preliminary proof-of-concept for efficient targeting of ERα by E2-Pt(II) linked chemotherapeutic hybrids.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2516. doi:10.1158/1538-7445.AM2011-2516