Inhibitors of 17β-hydroxysteroid dehydrogenase type 3 in the treatment of prostate cancer

INHIBITORS OF 17Î’-HYDROXYSTEROID DEHYDROGENASE TYPE 3 IN THE TREATMENT OF PROSTATE CANCER Name Grade Course: Tutor`s Name: (September 30, 2011) Inhibitors of 17β-hydroxysteroid dehydrogenase type 3 in the treatment of prostate cancer Abstract 17 ß-hydroxysteroid dehydrogenase (17ß-HSD) type 3 is an enzyme found in high amounts in the testes and plays a major role in biosynthesis of androgens such as testosterone hormone which is responsible for both internal and physical male characteristics. The role of 17ß-HSD type 3 in Prostate cancer treatment has widely been studied with emphasis on the inhibitors of the enzyme. In normal cells, 17ß-HSD type 3 enzymes have binding sites on androgen receptors on to which they bind and enhance transcription of genes that facilitate their multiplication. In cancer, the activity of 17ß-HSD type 3 has been observed to be much higher as compared to normal cells and gene transcription for the enzyme occurs in 15 minutes or less. Various studies show that inhibitors do exist that compete for the 17ß-HSD type 3 binding sites on the androgen receptors and others that block the enzymes from binding onto the androgen receptors, these have been broadly divided into two groups namely steroidal and non-steroidal inhibitors. By so doing the inhibitors alter the activity of 17ß-HSD type 3 hence reducing the amount of testosterone in blood and in the prostate. Many existing prostate cancer treatment modes including castration aim at lowering the levels of testosterone and following the fact that many inhibitors leading to the same effect exist, prostate cancer treatment can be enhanced through this manner. Introduction 17 ß-hydroxysteroid dehydrogenases (17ß-HSD) are enzymes found in humans and other animals such as rats; they are common in the testes, placenta and ovaries (Penning, 1996). The 17 ßHSD exist as isoenzymes and in general are responsible for the biosynthesis of the male and female sex hormones testosterone and estrogen, they catalyze the last step in the formation of these hormones. The common isoforms of the 17-ßHSD are namely type 1, type 2 , type 3 and type 4 and type 5, although other types up to type 15 exist. The type 3 17ß-HSD have been observed to be largely located in the testes prostate and seminal vesicles (Vicker, Sharland & Heaton et al, 2008). In the testes, the type 3 17ß-HSD plays an important role in synthesis of androgens by converting the 4-di-one substrate into testosterone. Given the significant role of the 17ß-HSD type 3 in biosynthesis of testosterone, there has been an increased interest in this particular type of 17ß-HSD with relation to treatment of prostate cancer because the androgen receptor has been observed to provide room for further growth and spread or prostate tumors (Narizhneva, Tararova & Ryabokon et al, 2009). Various researches show that inhibition of 17ß-HSD type 3 leads to production of low levels of androgens or none at all hence an effective anti-cancer mechanism. This paper will discuss of the inhibitors of 17ß-HSD type 3 especially in treatment of prostate cancer. Discussion 17ß-HSD type 3 is so crucial for the normal development of males such that any slight defects in the enzyme lead to various abnormalities such as pseudohermaphroditism which is a condition where the affected person exhibits dual sexual organs. The mechanism of such abnormalities has been explained as one that originates at the androgen receptors whereby the receptor activity is altered hence leading to a halt in development of male organs (Luu-The, Be´langer & Labrie, 2008, p 209). This shows that the androgens (testosterone and dihydrotestosterone) are no longer synthesized hence an implication that the two hormones possibly share the same androgen receptor. Similarly, androgen receptors have been identified to be central in the formation of prostate cancer, Narizhneva et al. (2009) emphasizes that these receptors are characteristic of prostatic cells and are vital for the survival and progression of the cancerous cells. As an assumption, most of the inhibitors of 17ß-HSD type 3 should be targeting the androgen receptors, but this will be proved in the discussion of various inhibitors. Evidence shows that the activity of 17ß-HSD type 3 is high in prostate cancer cells hence accelerating cancerous growth (Day, Tutill, & Foster et al, 2008); inhibition of the enzymes can be beneficial in arresting prostate cancer. Inhibitors of 17ß-HSD type 3 can broadly be categorized as steroidal and non-steroidal inhibitors. The difference between the two is the structure and mode of action; steroidal inhibitors have a structure that mimics that of the steroids and they compete for binding sites on the androgens just in the same manner as the androgens while non-steroidal inhibitors have other forms of structures such as phenyls and alkyl and generally they cause structural changes on the androgen receptors hence making it difficult or impossible for the androgens to bind on to them (Namiki, Kitagawa, Mizokami & Koh, 2008). Steroidal inhibitors were identified as early as 1983, they include 17-dione, 4-estrene-3, 5-androstene-3, phenyl and phenyl-CH2, Cyclohexyl- CH2 - CH2 among others; for most of these inhibitors, concentrations of as low as 10µm had inhibitory effects of greater than 95% either entirely or selectively (Bailey, 2007, p31-32). Non-steroidal inhibitors include compounds such as flavones, coumarins, p-benzoquinones among others. Most of non-steroidal inhibitors were observed to have increased regulatory activity in low potent cells (Bailey, 2007, p 35); this would be an entry point for cancer treatment as some of the non-steroidal inhibitors would be modified to enhance therapeutic potentials. Examples of non-steroidal drugs that have been used in cancer treatment include ...