5α-reductase for Prostate Cancer Prevention and Treatment

Abstract and Introduction

Abstract

Testosterone is the most abundant circulating androgen, and can be converted to dihydrotestosterone (DHT), a more potent androgen, by the 5α-reductase enzymes in target tissues. Current treatments for prostate cancer consist of reducing androgen levels by chemical or surgical castration or pure antiandrogen therapy that directly targets the androgen receptor (AR). Although these therapies reduce tumor burden and AR activity, the cancer inevitably recurs within 18–30 months. An approach targeting the androgen–AR axis at different levels could, therefore, improve the efficacy of prostate cancer therapy. Inhibition of 5α-reductase is one such approach; however, the two largest trials to investigate the use of the 5α-reductase inhibitors (5ARIs) finasteride and dutasteride in patients with prostate cancer have shown that, although the incidence of cancer was reduced by 5ARI treatment, those cancers that were detected were more aggressive than in patients treated with placebo. Thus, the best practice for using these drugs to prevent and treat prostate cancer remains unclear.

Introduction

Prostate cancer is the most frequently diagnosed cancer and the third most common cause of cancer-related deaths among men in developed countries.^[1] Prostate cancer-related deaths have declined over the past decade, owing to improved methods for early detection and diagnosis and more-effective therapeutic strategies.

Deregulation of the androgen–androgen receptor (AR) pathway is a hallmark of prostate cancer.^[2,3] Testosterone, the most abundant circulating androgen, is converted to dihydrotestosterone (DHT), which has a greater affinity for the AR than testosterone, by the 5α-reductase isoenzymes.^[4–7] During embryogenesis and throughout adulthood, androgens mediate the development, growth and maintenance of the male genitalia and secondary sexual characteristics.^[6] In addition to their importance in normal physiology, androgens also have a key role in the genesis and progression of diseases such as benign prostatic hyperplasia (BPH) and prostate cancer.^[8–10]

The steroid biosynthetic pathway involves the sequential enzymatic modification of the common precursor cholesterol to generate androgens, estrogens, progestogens and corticosteroids (Figure 1).^[11] Androgens—19-carbon compounds that form a subset within the steroid biosynthetic pathway—control development, growth and maintenance of male sexual characteristics.^[6,11] Testosterone is synthesized in the testis by the Leydig cells under the control of luteinizing hormone (LH) from the pituitary gland, internalized in prostate cells by passive diffusion, and converted to DHT by the 5α-reductase isoenzymes. The proposed mechanism of conversion of testosterone to DHT requires a reducing cofactor that will act as a hydride donor to the testosterone. For 5α-reductase, the cofactor is membrane-bound nicotinamide dinucleotide phosphate (NADPH). 5α-reductase forms a complex with NADPH that interacts with the substrate forming a ternary complex. The hydride from NADPH is transferred to carbon-5 of the aromatic ring, forming DHT. Once DHT is released, the 5α-reductase–NADP⁻ binary complex dissociates, and the enzyme can catalyze a new reaction.^[12]

(Enlarge Image)

Figure 1.

The steroidogenesis pathway. The common precursor cholesterol is sequentially modified by the enzymes to synthesize the steroid hormones. Testosterone is converted to its more potent form, DHT, by the 5α-reductase enzymes. Abbreviations: DHT, dihydrotestosterone; HSD, hydroxysteroid dehydrogenase.

There are three isoforms of the 5α-reductase enzymes, encoded by different genes and with differential expression patterns. The type 1 isoform is encoded by a gene on chromosome 5 and is expressed primarily in skin and liver.^[13,14] The gene encoding type 2 5α-reductase is on chromosome 2 and is expressed predominantly in stromal and basal epithelial cells of the prostate.^[13–15] Deficiency of type 2 5α-reductase, but not type 1, results in a lack of development of accessory sex organs.^[16,17] Interestingly, in prostate cancer, expression of both of these isoforms is increased, which could contribute to the enlargement of the organ.^[18,19] The type 3 5α-reductase isoenzyme is ubiquitously expressed in androgenic and nonandrogenic tissues, and elevated levels are found in prostate cancer cell lines.^[20–22] Type 3 5α-reductase reduces polyprenols to dolichols, which have a role in N-linked protein glycosylation, an essential post-translational modification to target proteins for secretion or membrane localization.^[23] No work has been published on the function of type 3 5α-reductase in prostate cancer.

Both testosterone and DHT are natural ligands of the AR, a member of the steroid nuclear receptor superfamily. Although the association rates of androgens to the AR are similar, DHT dissociates from the AR at a much slower rate, resulting in a more stable and active DHT–AR complex. DHT is, therefore, a more potent activator of AR than its precursor, testosterone.^[24–26] Indeed, animal models lacking 5α-reductase enzymes and humans with a mutation in the 5α-reductase gene (resulting in an inactive enzyme) display impaired development of male sexual organs, highlighting the importance of DHT synthesis in male physiology.^[6,27,28]

This Review will summarize the current knowledge of the role of testosterone and DHT in prostate disease and discuss the rationale for using treatments that target the synthesis of DHT in the treatment of prostate cancer. We will also bring together the data from the two largest trials of 5α-reductase inhibitors (5ARIs) in prostate cancer, and consider the future of these drugs in clinical practice.

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