Abstract
Pituitary Gonadotropin-Releasing Hormone receptors (GnRH-R) mediate the activity of the hypothalamic decapeptide GnRH, thus playing a key role in the regulation of the reproductive axis. Early-stage prostate cancer (PCa) is dependent on serum androgen levels, and androgen-deprivation therapy (ADT), based on GnRH agonists and antagonists, represents the standard therapeutic approach for PCa patients. Unfortunately, the tumor often progresses towards the more aggressive castration-resistant prostate cancer (CRPC) stage. GnRH receptors are also expressed in CRPC tissues, where their binding to both GnRH agonists and antagonists is associated with significant antiproliferative/proapoptotic, antimetastatic and antiangiogenic effects, mediated by the Gαi/cAMP signaling cascade. GnRH agonists and antagonists are now considered as an effective therapeutic strategy for CRPC patients with many clinical trials demonstrating that the combined use of these drugs with standard therapies (i.e., docetaxel, enzalutamide, abiraterone) significantly improves disease-free survival. In this context, GnRH-based bioconjugates (cytotoxic drugs covalently linked to a GnRH-based decapeptide) have been recently developed. The rationale of this treatment is that the GnRH peptide selectively binds to its receptors, delivering the cytotoxic drug to CRPC cells while sparing nontumor cells. Some of these compounds have already entered clinical trials.
Highlights
Gonadotropin-releasing hormone (GnRH) is the hypothalamic decapeptide known to play a central role in the control of the hypothalamicpituitary-axis in mammals [1,2,3,4]
GnRH receptors are expressed in castration-resistant prostate cancer (CRPC) tissues, where their binding to both GnRH agonists and antagonists is associated with significant antiproliferative/proapoptotic, antimetastatic and antiangiogenic effects, mediated by the Gαi/cAMP signaling cascade
It is produced by a small number of hypothalamic neurons and released in a pulsatile way into the hypophyseal circulation to reach the gonadotropes in the anterior pituitary where it binds to its specific receptors (GnRH-R)
Summary
Gonadotropin-releasing hormone (GnRH) is the hypothalamic decapeptide (pGlu-His-TrpSer-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) known to play a central role in the control of the hypothalamicpituitary-axis in mammals [1,2,3,4] It is produced by a small number of hypothalamic neurons and released in a pulsatile way into the hypophyseal circulation to reach the gonadotropes in the anterior pituitary where it binds to its specific receptors (GnRH-R). A GnRH-III decapeptide was found in sea lamprey (Petromyzon marinus) with an amino acid sequence that differs from that of GnRH in positions 5–8 (His, Asp, Trp, Lys8) [32] This peptide was reported to be endowed with a very low LH and FSH-stimulating activity in rats [33]. The GnRH decapeptide was shown to be expressed in these tumors, demonstrating the existence of an autocrine GnRH/GnRH receptor loop endowed with antitumor activity and supporting the role of this loop as an effective molecular target for anticancer strategies
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