title: VP-128, a novel oestradiol-platinum(II) hybrid with selective anti-tumour activity towards hormone-dependent breast cancer cells in vivo.
abstract: We have previously reported the synthesis of VP-128, a new 17beta-oestradiol (E(2))-linked platinum(II) hybrid with high affinity for oestrogen receptor alpha (ERalpha). 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 ERalpha-positive (MCF-7) and -negative (MDA-MB-468) cells as a model for treatment with increasing doses of VP-128, cisplatin or E(2) 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 ERalpha-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 ERalpha-dependent manner, inactivated both X-linked inhibitor of apoptosis protein and Akt, and induced selective nuclear accumulation of ERalpha and the expression of ER-regulated genes c-myc and tff1, which was blocked by ERalpha-specific antagonist ICI 282 780. In the case of ERalpha-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 ERalpha-positive and -negative breast cancer cells, and highlight the promising therapeutic value of this unique E(2)-platinum hybrid for selective targeting of hormone-dependent cancers.
authors: 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, Québec, Canada.
authors: Céline
authors: C
authors: Van Themsche
authors: Sophie
authors: S
authors: Parent
authors: Valérie
authors: V
authors: Leblanc
authors: Caroline
authors: C
authors: Descôteaux
authors: Anne-Marie
authors: AM
authors: Simard
authors: Gervais
authors: G
authors: Bérubé
authors: Eric
authors: E
authors: Asselin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004958:Estradiol / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions; D014407:Tumor Cells, Cultured; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D047628:Estrogen Receptor alpha; D009944:Organoplatinum Compounds; D012333:RNA, Messenger; D051636:X-Linked Inhibitor of Apoptosis Protein; D004958:Estradiol; D053148:Caspase 3