Potential impact of combined inhibition of 3α-oxidoreductases and 5α-reductases on prostate cancer

Abstract

Prostate cancer (PCa) growth and progression rely on the interaction between the androgen receptor (AR) and the testicular ligands, testosterone and dihydrotestosterone (DHT). Almost all men with advanced PCa receive androgen deprivation therapy (ADT). ADT lowers circulating testosterone levels, which impairs AR activation and leads to PCa regression. However, ADT is palliative and PCa recurs as castration-recurrent/resistant PCa (CRPC). One mechanism for PCa recurrence relies on intratumoral synthesis of DHT, which can be synthesized using the frontdoor or primary or secondary backdoor pathway. Androgen metabolism inhibitors, such as those targeting 5α-reductase, aldo-keto-reductase family member 3 (AKR1C3), or cytochrome P450 17A1 (CYP17A1) have either failed or produced only modest clinical outcomes. The goal of this review is to describe the therapeutic potential of combined inhibition of 5α-reductase and 3α-oxidoreductase enzymes that facilitate the terminal steps of the frontdoor and primary and secondary backdoor pathways for DHT synthesis. Inhibition of the terminal steps of the androgen metabolism pathways may be a way to overcome the shortcomings of existing androgen metabolism inhibitors and thereby delay PCa recurrence during ADT or enhance the response of CRPC to androgen axis manipulation.

Recapitulation of prostate tissue cell type-specific transcriptomes by an in vivo primary prostate tissue xenograft model

“…Therefore, based on gene expression profiles, prostate tissue appears to have a weak capacity to convert DHEA to T or DHT, an observation that is consistent with our recent report that benign prostate tissue converted DHEA to DHT only if DHEA was present at a supra-physiological concentration of 3.5 μM [25]. Back-door and alternative back-door pathways also were proposed as mechanisms for prostate cancer tissue to produce DHT without production of T as an intermediate [52,53]. The key enzymes for the back-door and alternative back-door pathways were expressed in prostate tissue: HSD17β6 (predominantly expressed in epithelial and stromal cells); HSD17β10 (universally expressed in all three cell types); and AKR1C3 (expressed in all three cell types, but highest in endothelial cells from fresh prostate tissue) (Fig 8).…”

Overview of AKR1C3: Inhibitor Achievements and Disease Insights

“…49 The cytochrome P450 family 17 subfamily A polypeptide 1 (CYP17A1) inhibitor abiraterone acetate (Abi) is widely used for the treatment of CRPC. However, CYP17A1 is an upstream enzyme 50 of androgen synthesis and is also involved in the metabolism of glucocorticoid (GC) and mineralocorticoid (MC). When Abi impairs androgen production, it also disrupts glucocorticoid synthesis.…”

“…46 CYP17A1 inhibition appears to be too early in the pathway to allow for the complete inhibition of androgen. 50 New therapeutic strategies targeting the downstream enzymes may have more pronounced effects.…”

“…Fiandalo et al proposed that the use of new 3a-oxidoreductase inhibitors could be an approach for PC treatment. 50 They attenuated the final steps of the primary and secondary backdoor androgen metabolic pathways. A combination of 3a-oxidoreductase, steroid 5α-reductase type 1 (SDR5A1), and CYP17A1 inhibition can achieve the greatest disruption of DHT production, bringing a new approach to surmount PC recurrence.…”

In honor of Dr. Donald S. Coffey – Prostate cancer biology and therapy

“…Another mechanism for PCa recurrence relies on intratumoral synthesis of dihydrotestosterone (DHT), which can be synthesized using the frontdoor, primary backdoor, or secondary backdoor pathway. Dr. James L. Mohler and his colleagues [6] described the therapeutic potential of combined inhibition of 5α-reductase and 3α-oxidoreductase enzymes that facilitate the terminal steps of these pathways for DHT synthesis. Inhibition of the terminal steps of the androgen metabolism pathways may be a way to overcome the shortcomings of existing androgen metabolism inhibitors and thereby delay PCa recurrence during ADT or enhance the response of CRPC to androgen axis manipulation.…”