Abiraterone Inhibits 3β-Hydroxysteroid Dehydrogenase: A Rationale for Increasing Drug Exposure in Castration-Resistant Prostate Cancer

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 3b-hydroxyl, D 5 -structure, we hypothesized that abi also inhibits 3b-hydroxysteroid dehydrogenase/isomerase (3bHSD), 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 3bHSD activity, androgen receptor localization, expression of androgen receptor-responsive genes, and CRPC growth in vivo.Results: Abi inhibits recombinant 3bHSD activity in vitro and endogenous 3bHSD activity in LNCaP and LAPC4 cells, including conversion ofandrogen receptor nuclear translocation, expression of androgen receptor-responsive genes, and xenograft growth in orchiectomized mice supplemented with DHEA. Abi also blocks conversion of D 5 -androstenediol to testosterone by 3bHSD. Abi inhibits 3bHSD1 and 3bHSD2 enzymatic activity in vitro; blocks conversion from DHEA to androstenedione and DHT with an IC 50 value of less than 1 mmol/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 3bHSD-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);

Anticancer Activity of a Novel Selective CYP17A1 Inhibitor in Preclinical Models of Castrate-Resistant Prostate Cancer

“…Decreasing concentrations of progesterone and increasing concentrations of pregnenolone occurred with higher doses of ABI, consistent with prior reports of HSD3B2 inhibition with higher doses of ABI (ref. 18; Fig. 3B).…”

Coregulation of srGAP1 by Wnt and Androgen Receptor Signaling: A New Target for Treatment of CRPC

“…Abiraterone Acetate and Enzalutamide) more effectively block androgen synthesis and to prevent activation of androgen receptor (AR) [7,8]. Although these AR targeting agents extend life of CRPC patients by a few months, resistance to these treatments remains common and currently there is no cure for CRPC [9][10][11][12][13][14][15][16][17][18]. Therefore, understanding the molecular mechanisms leading to CRPC and identifying alternative targets are important in developing more effective treatment for CRPC.…”

Circulating steroid hormone variations throughout different stages of prostate cancer

“…Abiraterone has to be co-administered with glucocorticoids as CYP17A1 inhibition results in enhanced ACTH-stimulation of the adrenal, which, in combination with the CYP17A1 block, causes significant accumulation of steroids with mineralocorticoid activity and consequently hypokalemia and hypertension (Pia et al 2013). Interestingly, abiraterone and its metabolite Δ4-abiraterone also act as inhibitors of 3β-hydroxysteroid dehydrogenase (3β-HSD) and as AR antagonists, respectively (Li et al 2012(Li et al , 2015.…”