title: Suppression of Delta(5)-androstenediol-induced androgen receptor transactivation by selective steroids in human prostate cancer cells.
abstract: Our earlier report suggested that androst-5-ene-3beta,7beta-diol (Delta(5)-androstenediol or Adiol) is a natural hormone with androgenic activity and that two potent antiandrogens, hydroxyflutamide (Eulexin) and bicalutamide (Casodex), fail to block completely the Adiol-induced androgen receptor (AR) transactivation in prostate cancer cells. Here, we report the development of a reporter assay to screen several selective steroids with anti-Adiol activity. Among 22 derivatives/metabolites of dehydroepiandrosterone, we found 4 steroids [no. 4, 1,3,5(10)-estratriene-17alpha-ethynyl-3, 17beta-diol; no. 6, 17alpha-ethynyl-androstene-diol; no. 8, 3beta, 17beta-dihydroxy-androst-5-ene-16-one; and no. 10, 3beta-methylcarbonate-androst-5-ene-7,17-dione] that have no androgenic activity and could also block the Adiol-induced AR transactivation in prostate cancer PC-3 cells. Interestingly, these compounds, in combination with hydroxyflutamide, further suppressed the Adiol-induced AR transactivation. Reporter assays further showed that these four anti-Adiol steroids have relatively lower glucocorticoid, progesterone, and estrogenic activity. Together, these data suggest some selective steroids might have anti-Adiol activity, which may have potential clinical application in the battle against the androgen-dependent prostate cancer growth.
authors.affiliation: George Whipple Laboratory for Cancer Research, Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA. chang@pathology.rochester.edu
authors.forename: H C
authors.initials: HC
authors.lastname: Chang
authors.forename: H
authors.initials: H
authors.lastname: Miyamoto
authors.forename: P
authors.initials: P
authors.lastname: Marwah
authors.forename: H
authors.initials: H
authors.lastname: Lardy
authors.forename: S
authors.initials: S
authors.lastname: Yeh
authors.forename: K E
authors.initials: KE
authors.lastname: Huang
authors.forename: C
authors.initials: C
authors.lastname: Chang
mesh_terms: D015114:Androstenediol / Q000037:antagonists & inhibitors*; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D013196:Dihydrotestosterone / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D003687:Dehydroepiandrosterone; D015114:Androstenediol