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This Article Full Text Full Text (PDF) All Versions of this Article: ERC-09-0113v1 16/4/1185    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Van Themsche, C. Articles by Asselin, E. Search for Related Content PubMed PubMed Citation Articles by Van Themsche, C. Articles by Asselin, E.

Research Group in Molecular Oncology and Endocrinology, Department of Chemistry and Biology, Canada Research Chair in Molecular Gyneco-Oncology, Université du Québec à Trois-Rivières, 3351, Boul. des Forges, CP 500, Trois-Rivières, Québec, Canada G9A 5H7

(Correspondence should be addressed to E Asselin; Email: eric.asselin{at}uqtr.ca)

We have previously reported the synthesis of VP-128, a new 17β-oestradiol (E₂)-linked platinum(II) hybrid with high affinity for oestrogen receptor (ER). In the present study, we have investigated the anti-tumour activity of VP-128 towards breast cancer cells in vitro and in vivo. We used human ER-positive (MCF-7) and -negative (MDA-MB-468) cells as a model for treatment with increasing doses of VP-128, cisplatin or E₂ in vitro and for xenograft experiments in nude mice in vivo. Compared with cisplatin, VP-128 showed markedly improved in vitro and in vivo anti-tumour activity towards ER-positive MCF-7 breast cancer cells, without increased systemic toxicity. In these caspase-3-deficient cells, treatment with VP-128 overcame weak cellular sensitivity to cisplatin in vitro and in vivo. In these cells, only the hybrid induced apoptosis in an ER-dependent manner, inactivated both X-linked inhibitor of apoptosis protein and Akt, and induced selective nuclear accumulation of ER and the expression of ER-regulated genes c-myc and tff1, which was blocked by ER-specific antagonist ICI 282 780. In the case of ER-negative MDA-MB-468 cells, VP-128, but not cisplatin, induced nuclear accumulation of apoptosis-inducing factor and inhibited c-myc expression. However, VP-128 did not show enhanced in vivo anti-tumour activity compared with cisplatin. These results reveal two different modes of action for VP-128 in ER-positive and -negative breast cancer cells, and highlight the promising therapeutic value of this unique E₂-platinum hybrid for selective targeting of hormone-dependent cancers.