Abstract
Gonadotropin-releasing hormone (GnRH) analogs (e.g., triptorelin) are developed to treat hormone-dependent reproductive cancers. However, these analogs lack a significant direct antitumor activity to make them suitable for hormone-refractory reproductive cancers. In this study, we examined different biological properties of lipid-modified GnRH analogs, with/without D-amino acid substitution at position 6 in prostate and ovarian cancer cells. We revealed that the improved metabolic stability due to lipid-modification and D-amino acid substitution played a pivotal role in enhancing GnRH receptor-mediated direct antiproliferative activity up to 4.5-fold higher than triptorelin. Furthermore, a comparable FSH release and higher LH release activity in pituitary cells than triptorelin was observed, indicating an improved specificity and/or binding affinity to GnRH receptors. We confirmed the important role of sex steroids in the antitumor activity of the lipopeptides, which were contrasting in prostate and ovarian cancer cells. The superior activity of these GnRH analogs over commercial peptides renders promises for developing new GnRH receptor ligands to treat hormone-dependent and -refractory cancers, as well as emerging new targeting moieties for the delivery of anticancer agents in GnRH receptor-overexpressing cancers.
Highlights
The primary regulatory component of the reproductive system is a gonadotropin-releasing hormone (GnRH), known as luteinizing hormone-releasing hormone (LHRH)
We showed that the improved stability due to lipid-modification and D-amino acid substitution played a pivotal role in enhancing Gonadotropin-releasing hormone (GnRH) receptormediated direct antiproliferative activity and gonadotropin-releasing potency
We previously showed that our developed lipid-modified GnRH analogs exhibited higher metabolic stability than the currently available agonist triptorelin and the natural GnRH receptor ligand (Table 1)
Summary
The primary regulatory component of the reproductive system is a gonadotropin-releasing hormone (GnRH), known as luteinizing hormone-releasing hormone (LHRH). The continuous administration of GnRH leads to the inhibition of the hypophyseal-gonadal axis via down-regulation, desensitization, and consequent suppression of GnRH receptors in the pituitary [6] It suppresses the secretion levels of LH, FSH, and sex steroids through a reversible medical castration process. We further investigated whether this increased stability and permeability of the lipid-modified GnRH analogs would lead to a better direct antitumor activity and gonadotropin release This might offer extra benefit for application in hormone-dependent cancers and make the new agonist(s) in addition to applications in hormoneresistant cancers of, e.g., prostate and ovary. Such analogs with improved stability will be suitable to be used as a targeting moiety in different drug delivery systems. The impact of sex steroids (dihydrotestosterone, DHT, or 17ß-estradiol, E2) on the direct antitumor activities of the GnRH analogs was investigated
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