VP-128, a novel oestradiol-platinum(II) hybrid with selective anti-tumour activity towards hormone-dependent breast cancer cells in vivo.
Endocr Relat Cancer
; 16(4): 1185-95, 2009 Dec.
Article
en En
| MEDLINE
| ID: mdl-19661132
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Compuestos Organoplatinos
/
Neoplasias de la Mama
/
Estradiol
/
Neoplasias Hormono-Dependientes
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Endocr Relat Cancer
Asunto de la revista:
ENDOCRINOLOGIA
/
NEOPLASIAS
Año:
2009
Tipo del documento:
Article
País de afiliación:
Canadá