TY - JOUR
T1 - Identification of steroid derivatives that function as potent antiandrogens
AU - Miyamoto, Hiroshi
AU - Marwah, Padma
AU - Marwah, Ashok
AU - Yang, Zhiming
AU - Chung, Chin Ying
AU - Altuwaijri, Saleh
AU - Chang, Chawnshang
AU - Lardy, Henry
PY - 2005/12/10
Y1 - 2005/12/10
N2 - 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, 3β-acetoxyandrosta- 1,5-diene-17-one ethylene ketal (ADEK), with some estrogenic activity. Here we report the identification of 2 additional steroid derivatives, 3β-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.
AB - 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, 3β-acetoxyandrosta- 1,5-diene-17-one ethylene ketal (ADEK), with some estrogenic activity. Here we report the identification of 2 additional steroid derivatives, 3β-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.
KW - Androgen receptor, antiandrogens
KW - Antiandrogen withdrawal syndrome
KW - Prostate cancer
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U2 - 10.1002/ijc.21217
DO - 10.1002/ijc.21217
M3 - Article
C2 - 15981214
AN - SCOPUS:27744443765
SN - 0020-7136
VL - 117
SP - 866
EP - 872
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 5
ER -