6-Chloromelatonin australia br Disclosure br Acknowledgement

Disclosure
Acknowledgement
Introduction CYP17A1 is a multifunctional enzyme with both 17α-hydroxylase and 17,20-lyase activities and is essential for the biosynthesis of steroidal 6-Chloromelatonin australia in male testes and adrenal glands. The 17α-hydroxylase activity of CYP17A1 is involved in the conversion of pregnenolone and progesterone to 17α-hydroxypregnenolone and 17α-hydroxyprogesterone, respectively, while the 17,20-lyase activity is involved in the side-chain cleavage of these 17α-hydroxysteroids to yield dehydroepiandrosterone (DHEA) and androstenedione, respectively, which are precursors of more potent androgens such as testosterone and dihydrotestosterone [1], [2], [3]. In rat testes, testosterone is synthesized mainly from progesterone by CYP17A1 [4]. Androgens stimulate the growth of hormone-sensitive prostate cancer (HSPC) [5], [6]. Standard treatment options for HSPC include surgical or medical castration, which eliminates androgens derived from the testes. However, HSPC often becomes resistant to this therapeutic tactic within a few years [7]. One hypothesis suggests that adrenal androgens that are not eliminated by castration play a role in the progression of prostate cancer (PC) to a castration-resistant state. This speculation is based on the findings that human adrenal glands, unlike those in rats, produce androgens such as DHEA and androstenedione [8] and that DHEA treatment stimulates the growth of androgen-refractory PC xenografts in nude mice [9]. Recently, the “intracrine” production of intratumoral androgens via the de novo synthetic route has also been proposed as being partially responsible for the progression of PC to a castration-resistant state (CRPC; [10], [11], [12]). Results from a phase 3 trial showed that abiraterone acetate, a steroidal CYP17A1 inhibitor of both 17α-hydroxylase and 17,20-lyase activities, prolonged overall survival in metastatic CRPC patients who had previously received chemotherapy [13], [14]. Therefore, CYP17A1 inhibitors have been validated as effective therapeutic targets in the treatment of PC. In developing a CYP17A1 inhibitor, high specificity toward inhibition of the 17,20 lyase activity is necessary to escape from serious side effects associated with 17α-hydroxylase inhibitions, such as inhibition of glucocorticoid synthesis. Recently, data from phase 1/2 clinical trials with orteronel (TAK-700), a novel, non-steroidal, selective 17,20 lyase inhibitor (Fig. 1), has shown it to be tolerable in patients with metastatic and non-metastatic CRPC when orally administered with or without prednisone [15], [16], [17], [18], and a dose of 400mg twice daily plus prednisone is being further evaluated in phase 2 and 3 studies [19], [20]. In the present study, we investigated the inhibitory activity of orteronel on androgen biosynthesis in rats, in particular its specificity for various androgen synthesis enzymes. We conducted our experiments using rat enzyme assays, rat testicular and adrenal cell assays, and in vivo using intact male rats, noting that the androgen synthesis pathway in rats is largely reflective of that in humans (Fig. 2). In addition, a human adrenocortical tumor cell line was used.
Materials and methods
Results and discussion Steroid hormone synthesis pathways are now well established in mammalian species. In rats, cholesterol is converted to pregnenolone, by the cholesterol side-chain cleavage P450scc enzyme, and subsequently metabolized to progesterone by 3β-hydroxysteroid dehydrogenase in the testes and adrenal glands (Fig. 2). In rat testes, progesterone undergoes 17α-hydroxylation and subsequently cleavage of the C17-20 bond by 17α-hydroxylase and 17,20-lyase, respectively, to yield androstenedione, which is converted by 17β-hydroxysteroid dehydrogenase to the androgen, testosterone. However, in rat adrenal glands, progesterone undergoes 21-hydroxylation and subsequently 11β-hydroxylation by the 21-hydroxylase and 11β-hydroxylase, respectively, to yield the main glucocorticoid, corticosterone. Corticosterone is further converted to the mineralocorticoid, aldosterone (Fig. 2).