Abiraterone
Brand Name: Zytiga, Yonsa, Akeega
Abiraterone is used to treat metastatic castration-resistant prostate cancer.1,2,3
How Does Abiraterone Work?
Testosterone is a hormone that promotes the development and maintenance of male sexual organs, including the prostate.4 Testosterone is also implicated in a variety of prostate-associated diseases. One such disease is prostate cancer, which commonly depends on testosterone for its survival and growth.5,6
In our body, testosterone is produced via a multi-step process. One key step in this process is the conversion of progesterone to androstenedione, which is catalyzed by an enzyme called CYP17A1.7
This enzymatic reaction broadly involves three steps. First, progesterone binds to CYP17A1. Second, CYP17A1 catalyzes the conversion of progesterone to androstenedione. Third, androstenedione is released from CYP17A1. The release of the product is crucial as it frees up CYP17A1 to participate in additional enzymatic reactions to produce more androstenedione.
Abiraterone is a drug with a similar structure to progesterone and is able to bind CYP17A1.8 However, abiraterone binds much tightly with the enzyme, and essentially gets "stuck".9
This prevents CYP17A1 from participating in further enzymatic reactions to produce more androstenedione. Since androstenedione, a direct precursor molecule of testosterone, is depleted, testosterone production ceases as well.10
Ultimately, the depletion of testosterone halts the growth of testosterone-dependent prostate cancer cells and results in their death.11
References
1. ZYTIGA. U.S. Food and Drug Administration (2011).
2. YONSA. U.S. Food and Drug Administration (2018).
3. AKEEGA. U.S. Food and Drug Administration (2023).
4. Mooradian, A. D., Morley, J. E. & Korenman, S. G. Biological Actions of Androgens. Endocrine Reviews 8(1), 1-28 (1987).
5. Huggins, C. & Hodges, C. V. Studies on Prostatic Cancer. I. The Effect of Castration, of Estrogen and of Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of the Prostate. Cancer Research 1(4), 293-297 (1941).
6. Dehm, S. M. & Tindall, D. J. Androgen Receptor Structural and Functional Elements: Role and Regulation in Prostate Cancer. Molecular Endocrinology 21(12), 2855-2863 (2007).
7. Miller, W. L. & Auchus, R. J. The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders. Endocrine Reviews 32(1), 81-151 (2011).
8. DeVore, N. M. & Scott, E. E. Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001. Nature 482(1), 116-119 (2012).
9. Cheong, E. J. Y. et al. Slow-, Tight-Binding Inhibition of CYP17A1 by Abiraterone Redefines Its Kinetic Selectivity and Dosing Regimen. Journal of Pharmacology and Experimental Therapeutics 374(3), 438-451 (2020).
10. Yin, L. & Hu, Q. CYP17 inhibitors—abiraterone, C17,20-lyase inhibitors and multi-targeting agents. Nature Reviews Urology 11, 32-42 (2014).
11. Akakura, K. et al. Effects of intermittent androgen suppression on androgen-dependent tumors. Apoptosis and serum prostate-specific antigen. Cancer 71(9), 2782-2790 (1993).
