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C Van Themsche, Chimie-biologie, Universite du Quebec a Trois-Rivieres, Trois-Rivieres, Quebec, Canada
S Parent, Chimie-biologie, Universite du Quebec a Trois-Rivieres, Trois-Rivieres, Quebec, Canada
V Leblanc, Chimie-biologie, Universite du Quebec a Trois-Rivieres, Trois-Rivieres, Quebec, Canada
C Descôteaux, Chimie-biologie, Universite du Quebec a Trois-Rivieres, Trois-Rivieres, Quebec, Canada
A Simard, Chimie-biologie, Universite du Quebec a Trois-Rivieres, Trois-Rivieres, Quebec, Canada
G Bérubé, Chimie-biologie, Universite du Quebec a Trois-Rivieres, Trois-Rivieres, Quebec, Canada
E Asselin, Chimie-biologie, Universite du Quebec a Trois-Rivieres, Trois-Rivieres, Quebec, G9A5H7, Canada

Correspondence: Eric Asselin, Email: eric.asselin{at}uqtr.ca

Abstract

We have previously reported the synthesis of VP-128, a new 17β-estradiol-linked platinum(II) hybrid with high affinity for ERa. In the present study, we have investigated antitumour activity of VP-128 towards breast cancer cells in vitro and in vivo. We used human ERa-positive (MCF-7) and -negative (MDA-MB-468) cells as a model for treatment with increasing doses of VP-128, cisplatin or estradiol in vitro and for xenograft experiments in nude mice in vivo. Compared to cisplatin, VP-128 showed markedly improved in vitro and in vivo antitumour activity towards ERa-positive MCF-7 breast cancer cells, without increased systemic toxicity. In these caspase-3-deficient cells, treatment with VP-128 overcomed weak cellular sensitivity to cisplatin, in vitro and in vivo. In these cells, only the hybrid induced apoptosis in an ERa-dependent manner, inactivated both XIAP (X-linked inhibitor of apoptosis protein) and Akt, and induced selective nuclear accumulation of ERa and the expression of ER-regulated genes c-myc and tff1, which was blocked by ERa-specific antagonist ICI 282780. In the case of ERa-negative MDA-MB-468 cells, VP-128, but not cisplatin, induced nuclear accumulation of AIF (apoptosis-inducing factor) and inhibited c-myc expression. However, VP-128 did not show enhanced in vivo antitumour activity compared to 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.