Identification of steroid derivatives that function as potent antiandrogens.
We have hypothesized that some steroid derivatives bind to the androgen receptor (AR) with very low androgenic activity and therefore potentially function as better AR antagonists than clinically used antiandrogens, such as flutamide. Indeed, we previously found such a compound, 3beta-acetoxyandrosta-1,5-diene-17-one ethylene ketal (ADEK), with some estrogenic activity. Here we report the identification of 2 additional steroid derivatives, 3beta-hydroxyandrosta-5,16-diene (HAD) and androsta-1,4-diene-3,17-dione-17-ethylene ketal (OAK), as new potent antiandrogens. Like ADEK, HAD and OAK could interrupt androgen binding to the AR and suppress both dihydrotestosterone- and androstenediol-induced transactivations of wild-type and mutant ARs in prostate cancer cells. These 2 compounds also inhibited prostate-specific antigen expression in LNCaP as well as growth of different AR-positive prostate cancer cell lines stimulated by androgen. Significantly, HAD and OAK had only marginal agonist effects, as compared to hydroxyflutamide. More importantly, in contrast to ADEK, OAK was shown to possess marginal estrogenic activity. These results strengthen our hypothesis and suggest that selective steroid derivatives could be potent antiandrogenic drugs with less unfavorable effects for the treatment of prostate cancer.
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA. Hiroshi_Miyamoto@urmc.rochester.edu
Hiroshi
H
Miyamoto
Padma
P
Marwah
Ashok
A
Marwah
Zhiming
Z
Yang
Chin-Ying
CY
Chung
Saleh
S
Altuwaijri
Chawnshang
C
Chang
Henry
H
Lardy
D000726:Androgen Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
D000726:Androgen Antagonists; D000728:Androgens; D011944:Receptors, Androgen; D017430:Prostate-Specific Antigen