Abiraterone Inhibits 3β-Hydroxysteroid Dehydrogenase: A Rationale for Increasing Drug Exposure in Castration-Resistant Prostate Cancer
Abiraterone Inhibits 3β-Hydroxysteroid Dehydrogenase: A Rationale for Increasing Drug Exposure in Castration-Resistant Prostate Cancer
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DOI：
10.1158/1078-0432.ccr-12-0908
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发表时间：
2012-07-01
影响因子：
11.5
通讯作者：
Sharifi, Nima
中科院分区：
文献类型：
--
作者：
Li, Rui;Evaul, Kristen;Sharifi, Nima
目的：醋酸阿比特龙（abi）治疗可提高去势抵抗性前列腺癌（CRPC）的生存率。对abi的抗性总是发生，可能部分是由于类固醇生成酶和/或维持二氢睾酮（DHT）合成的其他机制的上调，这增加了通过伴随抑制其他所需的类固醇生成酶来逆转抗性的可能性。基于3 β-羟基，δ（5）-结构，我们假设abi也抑制3 β-羟基类固醇脱氢酶/异构酶（3 β HSD），这是在CRPC中的DHT合成所绝对需要的，无论合成的来源或途径。我们测试了abi对3 β HSD活性、雄激素受体定位、雄激素受体应答基因表达结果：阿比特龙在体外抑制重组3 β HSD活性，在LNCaP和LAPC 4细胞中抑制内源性3 β HSD活性，包括[H-3]-脱氢表雄酮（DHEA）向δ（4）-雄烯二酮的转化、雄激素受体核转位、雄激素受体反应基因的表达以及补充DHEA的睾丸切除小鼠异种移植物的生长。阿比特龙还阻断了δ（5）-雄烯二醇通过3 β HSD转化为睾酮。阿比特龙在体外抑制3 β HSD 1和3 β HSD 2酶活性;阻断DHEA向雄烯二酮和DHT的转化，在CRPC细胞系中的IC 50值小于1 μ mol/L;抑制雄激素受体核转位;抑制TMPRSS 2、前列腺特异性抗原和FKBP 5的表达;并降低补充DHEA的小鼠中CRPC异种移植物的生长。我们的结论是，abi抑制CRPC中3 β HSA介导的DHEA转化为活性雄激素。这第二种作用模式可用于通过剂量递增或简单地通过与食物一起给药以增加药物暴露来逆转标准abi剂量下对CYP 17 A1抑制的耐药性。临床癌症研究; 18（13）; 3571-9。（C）2012年AACR。
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 3 beta-hydroxyl, Delta(5)-structure, we hypothesized that abi also inhibits 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta HSD), 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 3 beta HSD activity, androgen receptor localization, expression of androgen receptor-responsive genes, and CRPC growth in vivo.Results: Abi inhibits recombinant 3 beta HSD activity in vitro and endogenous 3 beta HSD activity in LNCaP and LAPC4 cells, including conversion of [H-3]-dehydroepiandrosterone (DHEA) to Delta(4)-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 Delta(5)-androstenediol to testosterone by 3 beta HSD. Abi inhibits 3 beta HSD1 and 3 beta HSD2 enzymatic activity in vitro; blocks conversion from DHEA to androstenedione and DHT with an IC50 value of less than 1 mu mol/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 3 beta HSD-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. (C)2012 AACR.