Potential prostate cancer drug target: bioactivation of androstanediol by conversion to dihydrotestosterone

Abstract

High-affinity binding of dihydrotestosterone (DHT) to the androgen receptor (AR) initiates androgen-dependent gene activation, required for normal male sex development in utero, and contributes to prostate cancer development and progression in men. Under normal physiologic conditions, DHT is synthesized predominantly by 5α-reduction of testosterone, the major circulating androgen produced by the testis. During androgen deprivation therapy, intratumoral androgen production is sufficient for AR activation and prostate cancer growth, even though circulating testicular androgen levels are low. Recent studies indicate that the metabolism of 5α-androstane-3α, 17β-diol by 17β-hydroxysteroid dehydrogenase 6 in benign prostate and prostate cancer cells is a major biosynthetic pathway for intratumoral synthesis of DHT, which binds AR and initiates transactivation to promote prostate cancer growth during androgen deprivation therapy. Drugs that target the so-called backdoor pathway of DHT synthesis provide an opportunity to enhance clinical response to luteinizing-hormone-releasing hormone (LHRH) agonists or antagonists, AR antagonists, and inhibitors of 5α-reductase enzymes (finasteride or dutasteride), and other steroid metabolism enzyme inhibitors (ketoconazole or the recently available abiraterone acetate).

Figure 1. Backdoor pathway of DHT synthesis involves the conversion of androstanediol to DHT by 17β-HSD6

Conversion of cholesterol to prenenolone by the P450 side chain cleavage enzyme (P450ssc) is the first committed step in steroid biosynthesis. The 17α-hydroxylase/17,20-lyase (P450c17) catalyzes multiple 17α-hydroxylase and 17,20-lyase reactions in the steroidogenic pathway that require P450 oxidoreductase (P450ox/red) electron transfer. P450c17 coded by the CYP17A1 gene is the target for inhibition by abiraterone acetate. Progesterone, 17α-hydroxyprogesterone (17α-OH-progesterone) and testosterone are substrates for 5α-reductase type 1, 2 or 3 (5αR1, 2 or 3). Finasteride is an 5αR2 inhibitor. Dutasteride is an inhibitor of 5αR1, 5αR2 and 5αR3. Isozymes of 3β-hydroxysteroid dehydrogenase (3βHSD), 17β-hydroxysteroid dehydrogenase (17βHSD) and aldo-keto reductase (AKR1C3) are often reversible enzymes with oxidative and reductive activities that require nicotinamide adenine dinucleotide cofactors. Testosterone and DHT are the two biologically active androgens that activate AR. Testosterone is the major circulating active androgen formed in the testis. DHT is formed from testosterone in the testis, and can be synthesized in a so-called backdoor pathway (green) from progesterone and androsterone precursors independent of DHEA, androstenedione or testosterone intermediates.