Send Orders for Reprints to reprints@benthamscience.net 66 Anti-Cancer Agents in Medicinal Chemistry, 2014, 14, 66-76 Genetics, Structure, Function, Mode of Actions and Role in Cancer Development of CYP17 Tatyana. A Sushko, Andrei A. Gilep * and Sergey A. Usanov Institute of Bioorganic Chemistry NASB, Belarus, 220141 Minsk, Belarus, Kuprevicha str. 5/2, Belarus Abstract: Most prostate and breast cancers are hormone dependent. The inhibition of steroid 17-hydroxylase/17,20- lyase (CYP17), which is a crucial enzyme for steroid hormone biosynthesis, is widely used to treat androgen-dependent prostate cancer (PC). CYP17 has dual enzymatic activity: 17alpha-hydroxylase activity (utilizing delta4- C21 steroids as substrates) and the 17,20-lyase activity (using delta5- C21 steroids as substrates). The steroid biosynthetic pathway is directed to either the production of corticosteroids or sex hormones depending on the activity of CYP17. In this review, the current information on the genetics, molecular structure, substrate specificity and inhibitors of CYP17 is analyzed and discussed. Keywords: Cytochrome P450, CYP17, hormone-dependent cancer, inhibitors of androgen biosynthesis, prostate cancer, steroid hormone biosynthesis, steroid 17-hydroxylase, 17,20-lyase. INTRODUCTION According to the data reported by the World Health Organization, death from cancer is the leading cause of death in the world, and cancer is supposed to cause more than 12 million deaths by the year 2030 [1]. Prostate cancer and breast cancer are the most prevalent types of cancer in men and women, respectively [2]. Most prostate and breast cancers are hormone dependent. Sex steroid hormones play significant role either in the normal development and functioning of these organs or in cancerous growths. Cytochrome P450s (CYPs) are essential enzymes, such as catalyzing the key steps in the biosynthetic pathway of steroid hormones. CYPs are also involved in biotransformation of several precarcinogens and in activation/inactivation of the antineoplastic drugs. Thus, CYPs are crucial for the cancer development and they are the promising targets for anti-cancer therapy. The development of potent inhibitors of aromatase (CYP19) which have been used to treat breast cancer was the first successful example of application of targeting CYP enzymes in anti-cancer therapy. The clinical success of aromatase inhibitors opened up a new direction in developing hormone ablation therapy for estrogen- dependent cancers and gave rise to similar strategies for CYP17 inhibition, which have become very valuable in treating androgen- dependent prostate cancer (PC) [3]. Hormone therapy (androgen deprivation therapy) is the main strategy for advanced PC [4], because androgens, including testosterone (T) and dihydrotestosterone (DHT), stimulate the growth of prostate cancer cells by activating the transcription of genes associated with cell proliferation and survival. Androgen suppression therapy is frequently combined with chemical or surgical castration. Due to the castration a decreased production of T and DHT by the testes is observed, but adrenal glands and the cancerous prostate gland itself still continue to produce androgens; it is also suggested that the adipose tissue and skin produce androgens; so as a result, cancer cells continue to grow [5]. Therefore, compounds which have high potencies in inhibiting androgen biosynthesis may prove to be more efficacious than castration in the treatment of PC. CYP17 (steroid 17- hydroxylase/17,20-lyase) plays a crucial role in the steroid hormone biosynthesis. CYP17 is unique because of its ability to catalyze two different types of reactions, the 17alpha -hydroxylase and *Address correspondence to this author at the Institute of Bioorganic Chemistry NASB Belarus, 220141 Minsk, Kuprevicha str. 5/2, Belarus; Tel/Fax: +375-17-263-7274; E-mail: agilep@iboch.bas-net.by 17,20-lyase reactions, in one active site,. Furthermore, the ratio of these reactions is physiologically important and may direct steroid hormone biosynthesis towards the production of corticoid or sex hormones. Thus, CYP17 is a highly promising target in the inhibition of androgen biosynthesis. THE CYP17A1 GENE The CYP17A1 gene is typical for the genomes of all Chordata species and encodes highly conserved cytochrome P450. The human gene is located in chromosome 10 at position 10q24.3 and spans over 10 kb [6]. Transcription initiation site is mapped approximately 180 bp upstream of the initiation codon in exon 1 and ~1.7 kb mRNA is produced. Recently, a number of studies have focused on genetic factors that may influence the risk of developing cancer. Much attention has been given to the study of polymorphic variants of the genes encoding enzymes that participate in sex hormone metabolism. It is suggested that variants of CYP17A1 may be associated with increased risk of hormone dependent cancer [7]. By now, more than 100 polymorphic variants of CYP17A1 have been identified; the majority of polymorphisms have been mapped to non-coding regions of the CYP17A1. In order to elucidate if CYP17A1 gene polymorphisms are associated with the risk of developing PC, many case-control studies have been carried out to answer this problem. However, the data obtained were contradictory [7, 8]. In the past years, the polymorphism -34T/C (rs743572) has attracted widespread attention because this polymorphism was postulated to be associated with changes in circulating concentrations of sex hormones and with an increased risk of breast, prostate or endometrial cancer [9]. Polymorphism rs743572, which is mapped to the 5’-untranslated promoter region of CYP17, creates a site of restriction endonuclease cleavage (restriction enzyme MspA1) giving rise to the two allelic variants: A1 (T, wild allele) and A2 (C, variant allele). A recently conducted meta-analysis [7] indicated that the rs743572 polymorphism is associated with increased risk of PC only in Black population. However, there is no significant relationship between rs743572 polymorphism and risk of PC in the general population, so this polymorphism might not be considered as a critical factor for PC susceptibility in humans. This fact supports the hypothesis that PC is a multigenic disease. At the same time, persons carrying A2 allele of CYP17 have a lower risk of developing pancreatic cancer [12]. Furthermore, 1875-5992/14 $58.00+.00 © 2014 Bentham Science Publishers