Effects of steroidal and non-steroidal antiandrogens on wild-type and mutant androgen receptors.
BACKGROUND
Molecular basis for secondary antiandrogen therapy in prostate cancer with mutant androgen receptors (ARs) is not fully elucidated.


METHODS
Effects of steroidal and non-steroidal antiandrogens on transcriptional activities of wild-type and mutant (W741C, T877A, and W741C+T877A) ARs were measured. Crystal structure analysis and docking studies were performed using Molecular Operating Environment (MOE) package.


RESULTS
DHT-induced transcriptional activity of the T877A mutant and the W741C mutant was suppressed by bicalutamide and hydroxyflutamide, respectively. Nilutamide suppressed the W741C mutant and the double mutant. Cyproterone acetate modestly inhibited the W741C mutant and the double mutant. The structural studies suggested that nilutamide and cyproterone acetate retain their antiandrogenic properties against both the W741C mutant and the double mutant due to fact that mutation W741C does not permit formation of key hydrophobic interaction between ligand and AR ligand binding domain, which is necessary for their conversion into agonists.


CONCLUSIONS
Switching antiandrogens may be reasonable in prostate cancer with mutant ARs.
Urushibara
Masayasu
M
Department of Urology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Ishioka
Junichiro
J
Hyochi
Nobuhiko
N
Kihara
Kazunori
K
Hara
Shuntaro
S
Singh
Pratap
P
Isaacs
John T
JT
Kageyama
Yukio
Y
D000500:Allylestrenol / Q000494:pharmacology; D000726:Androgen Antagonists / Q000737:chemistry / Q000494:pharmacology*; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000813:Anilides / Q000737:chemistry / Q000494:pharmacology; D017373:Cyproterone Acetate / Q000737:chemistry / Q000494:pharmacology; D005485:Flutamide / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D048289:Imidazolidines / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology; D010957:Plasmids / Q000235:genetics; D017430:Prostate-Specific Antigen / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013739:Testosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D014105:Tosyl Compounds / Q000737:chemistry / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000813:Anilides; D048289:Imidazolidines; D009570:Nitriles; D012334:RNA, Neoplasm; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C014290:hydroxyflutamide; D013739:Testosterone; D017373:Cyproterone Acetate; C021277:nilutamide; C013915:boldenone; D005485:Flutamide; C053541:bicalutamide; D017430:Prostate-Specific Antigen; D000500:Allylestrenol