摘要
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.
- 出版日期2012-7-1