Non-competitive steroid inhibition of oestrogen receptor functions.

Article Details

Citation

Copy to clipboard

Puddefoot JR, Barker S, Glover HR, Malouitre SD, Vinson GP

Non-competitive steroid inhibition of oestrogen receptor functions.

Int J Cancer. 2002 Sep 1;101(1):17-22.

PubMed ID

12209583 [ View in PubMed

]

Abstract

Currently available antioestrogens, such as tamoxifen, are competitive inhibitors that bind to the ligand binding sites of oestrogen receptors, ERalpha and ERbeta. The search for alternative anti-hormone therapies is prompted by the need for drugs that are effective when tumours become tamoxifen resistant. The existence of different receptor isoforms also raise the possibility of improving selectivity. Earlier use of the 3beta-hydroxysteroid dehydrogenase inhibitor, trilostane (4alpha,5- epoxy-17beta-hydroxy-3-oxo-5alpha-androstane-2alpha-carbonitrile), suggested that it had beneficial actions in breast cancer that were only partially attributable to inhibition of steroidogenesis. The present studies on the interactions of trilostane with oestrogen receptors show that it (i) inhibits oestrogen-stimulated proliferation in MCF-7 breast cancer cells, (ii) enhances the affinity of oestradiol binding to ER in rat uteri and specifically increases oestradiol binding to an ERbeta-like isoform, (iii) inhibits ERalpha and ERbeta binding to the classical vitellogenin gene oestrogen response element (ERE) and (iv) inhibits oestrogen-stimulated gene transcription in ERE-linked reporter systems in MCF-7 cells. The results demonstrate a novel, presumably allosteric, mode of antioestrogen action. The beneficial actions of trilostane in breast cancer may be attributed to the combination of this antioestrogen effect with its well documented suppression of steroidogenesis.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Trilostane	Estrogen receptor alpha	Protein	Humans	Yes	Allosteric modulator	Details
Trilostane	Estrogen receptor beta	Protein	Humans	Yes	Allosteric modulator	Details