A major hurdle in chemotherapy is cellular resistance, non-responsiveness to chemotherapeutic agents and important side effects. First-line chemotherapeutic use of cisplatin has been demonstrated in patients with advanced breast cancer for many years, but high dose-related side effects are due to the lack of cancer cell specificity. Breast cancer is the most commonly diagnosed cancer for women Worldwide and the 2nd leading cause of cancer death in North American woman. It is imperative to investigate novel targeted-strategy of treatment. A new family of 17β-estradiol-platinum(II) molecules have been synthesized which are linked with an alkyl chain at position 16α of the steroid nucleus and bear a 16β-hydroxymethyl side chain. The objective of the study was to determine the cytotoxic effect of these novel molecules using estrogen dependent (estrogen receptor positive; ER+) and independent (estrogen receptor negative; ER-) human breast cancer cells. Estrogen receptor binding studies showed a strong affinity of these molecules to the estrogen receptor (EC50 ranging from 1.1 and 4.2 nM compared to 0.7 nM for 17β-estradiol, the natural ligand). The biological activity of these compounds was evaluated in vitro using MTT cell proliferation assay and single cell apoptosis measurements were carried out using Hoechst nuclear staining. Most of the molecules tested showed inhibition of breast cancer cell proliferation and induction of apoptosis. Some of these molecules killed more efficiently ER+ cells when compared to ER- cells. The 17β-estradiol-platinum(II) molecules were 3 to 16 times more efficient to kill cells when compared to cisplatin IC50. In order to investigate and confirm apoptosis induction in MCF-7 (ER+) and MDA-MB-468 (ER-) cells following treatment with 17β-estradiol-platinum(II) molecules, Western blot analyses were carried out and showed an increase of cleaved caspase-8, caspase-9, caspase-3 (except for MCF-7) and PARP fragments in a dose-dependent manner. Nude mice bearing ER+ or ER- breast cancer cells xenografts treated with 17β-estradiol-platinum(II) molecules showed a striking tumor size reduction when compared to cisplatin-treated xenografted mice. Taken together these results suggest that these unique molecules might have a great potential for the treatment of breast cancers. Moreover, the use of these molecules as a treatment could be extended to other cancers expressing the estrogen receptor such as cervix, endometrial and ovarian cancers. Supported by CIHR (MOP-66987).

[Proc Amer Assoc Cancer Res, Volume 46, 2005]