title: 3 beta-acetoxyandrost-1,5-diene-17-ethylene ketal functions as a potent antiandrogen with marginal agonist activity.
abstract: The majority of available antiandrogens have been reported to possess agonist activity to induce prostate-specific antigen, which might result in antiandrogen withdrawal syndrome. Here we report the identification of 3 beta-acetoxyandrost-1,5-diene-17-ethylene ketal (ADEK) from dehydroepiandrosterone metabolites and derivatives as a potent antiandrogen. We found ADEK could interrupt androgen binding to the androgen receptor (AR) and suppress androgen-induced transactivations of WT AR and a mutant AR in prostate cancer cells. ADEK inhibited prostate-specific antigen expression as well as growth in LNCaP prostate cancer cells stimulated by androgen. Importantly, ADEK had only marginal agonist effects, as compared with commonly used antiandrogens such as hydroxyflutamide and bicalutamide, leading to a lower possibility of inducing withdrawal response. Moreover, ADEK could block an adrenal androgen androstenediol-induced AR transactivation that hydroxyflutamide and bicalutamide failed to block. These unique antiandrogenic activities make ADEK a potential therapeutic compound that might be able to inhibit AR-mediated prostate cancer progression. Further in vivo studies might facilitate the development of a better antiandrogen for the treatment of prostate cancer.
authors.affiliation: George Whipple Laboratory for Cancer Research, Department of Pathology, and The Cancer Center, University of Rochester, Rochester, NY 14642, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyamoto
authors.forename: Padma
authors.initials: P
authors.lastname: Marwah
authors.forename: Ashok
authors.initials: A
authors.lastname: Marwah
authors.forename: Henry
authors.initials: H
authors.lastname: Lardy
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D000726:Androgen Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000730:Androstadienes / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D017930:Genes, Reporter; D006801:Humans; D008297:Male; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D045165:Testosterone Congeners / Q000737:chemistry / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: C474317:3-acetoxyandrost-1,5-dien-17-ethylene ketal; D000726:Androgen Antagonists; D000730:Androstadienes; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D045165:Testosterone Congeners; D003687:Dehydroepiandrosterone; D017430:Prostate-Specific Antigen