CYP17 Inhibitors for Prostate Cancer Treatment – An Update

Abstract

It is almost 70 years since the discovery by Huggins et al. that androgens are essential for prostate cancer (PC) growth and progression, and there has been about 30 years experience using ketoconazole for PC therapy. Since then we have come a long way in learning about the disease and developing new strategies to approach it, among which is cytochrome 17alpha-hydroxylase-C(17,20)-lyase (CYP17) inhibition. This review focuses on the efforts to find prospective CYP17 inhibitors, both steroidal and nonsteroidal, in the absence of a 3D structure of the enzyme. It covers almost 4 decades of literature with highlights on the most significant achievements in this area, providing insight into PC pathophysiology, management and treatment options.

Highlights of Natural Products in Prostate Cancer Drug Discovery

“…It is also a leading cause of mortality and the second most common cause of cancer-related death in both the USA and Australia, and the third most common cause of cancer-related death in the European Union (Jemal et al, 2011, Jemal et al, 2010. PC is a hormone-sensitive cancer that is influenced by androgens such as testosterone, produced from cholesterol mainly in the testis but also in the adrenal glands as well as in other tissues including prostate tissue (Moreira et al, 2008, Schrijvers et al, 2010. Dihydrotestosterone, the main metabolite of testosterone, is the principal ligand for the androgen receptor (AR).…”

“…In case of progression, antiandrogen withdrawal results in response in about 5 to 20% of patients (Harzstark & Small, 2010). Other options include secondary hormonal therapy using mainly ketoconazole due to its ability to inhibit cytochrome P450 17-hydroxylase C 17,20 -lyase (CYP17), one of the enzymes responsible for the biosynthesis of androgen precursors in the human body (Moreira et al, 2008). Despite its efficacy and ease of administration, ketoconazole bears several side effects (De Felice et al, 1981, Lake-Bakaar et al, 1987.…”

Determination of 17α-hydroxylase-C17,20-lyase (P45017α) enzyme activities and their inhibition by selected steroidal picolyl and picolinylidene compounds

“…inhibition of P450 17α can block androgen synthesis, and may be competent in pharmacological treatment of hormone dependent disorders [4,16,18]. this enzyme is also a potential target for a drug designed to treat androgen dependent prostatic carcinoma [12,27]. inhibitory action was found to be related to lone electron pair coordination to the heme iron atom at the active site of the enzyme and many steroidal compounds bearing different heteroaromatic moieties on ring D of the sterane skeleton were analyzed against P450 17α .…”

Targeting Drug-Metabolizing Enzymes for Effective Chemoprevention and Chemotherapy

“…Success in any of these approaches will likely provide novel opportunities for maximizing the tumoricidal effects while minimizing the toxic side effects of chemopreventive and therapeutic agents. The current clinical success of aromatase (CYP19) inhibitors that are used to treat breast cancer (Jordan and Brodie, 2007) has led many investigators, including our research group, to question whether inhibitors of additional P450s may similarly be effective in treating other hormonally responsive cancers (Bruno and Njar, 2007;Moreira et al, 2008). With this in mind, the use of inhibitors of 17␣-hydroxylase/17,20-lyase (CYP17), a key multifunctional enzyme that lies at the crossroads of androgen and corticoid biosynthesis, holds considerable promise in treating prostate cancer.…”

“…With this in mind, the use of inhibitors of 17␣-hydroxylase/17,20-lyase (CYP17), a key multifunctional enzyme that lies at the crossroads of androgen and corticoid biosynthesis, holds considerable promise in treating prostate cancer. This approach is based on the knowledge that 1) androgens are strongly implicated in the progression of prostate cancer, 2) prostate cells as well as prostate cancer cells continuously produce androgens, and 3) systemic ablation of androgen is highly effective in treating prostate cancer (Bruno and Njar, 2007;Moreira et al, 2008;Harris et al, 2009).…”