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Targeting 5α-reductase for prostate cancer prevention and treatment

Nature Reviews Urology volume 8, pages 378–384 (2011)Cite this article

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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.

Key Points

  • Activation of the androgen receptor (AR) is crucial for tumor cell progression and survival of prostate cancer, and androgen deprivation therapy remains the main clinical approach in men with locally advanced tumors

  • Current therapies incompletely suppress the androgen–AR axis, but a multiple therapeutic approach, targeting androgens and their receptor, has potential to improve clinical outcomes

  • Treatment of prostate cancer cells with 5α-reductase inhibitors (5ARIs) inhibits cellular pathways regulating metabolism, cell growth and proliferation, triggering apoptosis and decreasing prostate size

  • Although 5ARI treatment reduces the risk of developing prostate cancer, patients treated with these drugs have tumors with higher Gleason scores than those who receive placebo

  • Use of 5ARIs to prevent and treat prostate cancer remains controversial, and further investigation is necessary to understand the presence of more-aggressive tumors in patients receiving these drugs

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Figure 1: The steroidogenesis pathway.
Figure 2: The role of DHT in different stages of prostate development and cancer.

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Acknowledgements

The authors receive support from NIH grants CA121277, CA91956, and CA125747. D. J. Tindall receives support from the T. J. Martell Foundation, grant DK65236 and L. P. Nacusi is the recipient of the Mayo Clinic Endocrinology, Diabetes, and Metabolism training grant.

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  1. Department of Urology Research, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA,

    Lucas P. Nacusi

  2. Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA,

    Donald J. Tindall

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Nacusi, L., Tindall, D. Targeting 5α-reductase for prostate cancer prevention and treatment. Nat Rev Urol 8, 378–384 (2011). https://doi.org/10.1038/nrurol.2011.67

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