前列腺癌
雄激素受体
脱氢表雄酮
内分泌学
内科学
二氢睾酮
雄激素
睾酮(贴片)
LNCaP公司
醋酸阿比特龙酯
化学
下调和上调
癌症研究
雄激素剥夺疗法
生物
医学
癌症
激素
生物化学
基因
作者
Rui Li,Kristen Evaul,Kamalesh Kumar Sharma,Kai-Hsiung Chang,Jennifer Yoshimoto,Jiayan Liu,Richard J. Auchus,Nima Sharifi
标识
DOI:10.1158/1078-0432.ccr-12-0908
摘要
Abstract Purpose: Treatment with abiraterone (abi) acetate prolongs survival in castration-resistant prostate cancer (CRPC). Resistance to abi invariably occurs, probably due in part to upregulation of steroidogenic enzymes and/or other mechanisms that sustain dihydrotestosterone (DHT) synthesis, which raises the possibility of reversing resistance by concomitant inhibition of other required steroidogenic enzymes. On the basis of the 3β-hydroxyl, Δ5-structure, we hypothesized that abi also inhibits 3β-hydroxysteroid dehydrogenase/isomerase (3βHSD), which is absolutely required for DHT synthesis in CRPC, regardless of origins or routes of synthesis. Experimental Design: We tested the effects of abi on 3βHSD activity, androgen receptor localization, expression of androgen receptor–responsive genes, and CRPC growth in vivo. Results: Abi inhibits recombinant 3βHSD activity in vitro and endogenous 3βHSD activity in LNCaP and LAPC4 cells, including conversion of [3H]-dehydroepiandrosterone (DHEA) to Δ4-androstenedione, androgen receptor nuclear translocation, expression of androgen receptor–responsive genes, and xenograft growth in orchiectomized mice supplemented with DHEA. Abi also blocks conversion of Δ5-androstenediol to testosterone by 3βHSD. Abi inhibits 3βHSD1 and 3βHSD2 enzymatic activity in vitro; blocks conversion from DHEA to androstenedione and DHT with an IC50 value of less than 1 μmol/L in CRPC cell lines; inhibits androgen receptor nuclear translocation; expression of TMPRSS2, prostate-specific antigen, and FKBP5; and decreases CRPC xenograft growth in DHEA-supplemented mice. Conclusions: We conclude that abi inhibits 3βHSD-mediated conversion of DHEA to active androgens in CRPC. This second mode of action might be exploited to reverse resistance to CYP17A1 inhibition at the standard abi dose by dose-escalation or simply by administration with food to increase drug exposure. Clin Cancer Res; 18(13); 3571–9. ©2012 AACR.
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