3β-acetoxyandrost-1,5-diene-17-ethylene ketal functions as a potent antiandrogen with marginal agonist activity

被引:16
作者
Miyamoto, H
Marwah, P
Marwah, A
Lardy, H
Chang, CS
机构
[1] Univ Rochester, George Whipple Lab Canc Res, Dept Pathol, Rochester, NY 14642 USA
[2] Univ Rochester, George Whipple Lab Canc Res, Dept Urol, Rochester, NY 14642 USA
[3] Univ Rochester, George Whipple Lab Canc Res, Dept Radiat Oncol, Rochester, NY 14642 USA
[4] Univ Rochester, Ctr Canc, Rochester, NY 14642 USA
[5] Univ Wisconsin, Dept Biochem, Inst Enzyme Res, Madison, WI 53726 USA
关键词
D O I
10.1073/pnas.0831001100
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 3beta-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.
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页码:4440 / 4444
页数:5
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