Abstract
Degarelix is a gonadrotropin-releasing hormone (GnRH) receptor (GnRHR) antagonist used in patients with prostate cancer who need androgen deprivation therapy. GnRHRs have been found in extra-pituitary tissues, including prostate, which may be affected by the GnRH and GnRH analogues used in therapy. The direct effect of degarelix on human prostate cell growth was evaluated. Normal prostate myofibroblast WPMY-1 and epithelial WPE1-NA22 cells, benign prostatic hyperplasia (BPH)-1 cells, androgen-independent PC-3 and androgen-dependent LNCaP prostate cancer cells, as well as VCaP cells derived from a patient with castration-resistant prostate cancer were used. Discriminatory protein and lipid fingerprints of normal, hyperplastic, and cancer cells were generated by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS). The investigated cell lines express GNRHR1 and GNRHR2 and their endogenous ligands. Degarelix treatment reduced cell viability in all prostate cell lines tested, with the exception of the PC-3 cells; this can be attributed to increased apoptosis, as indicated by increased caspase 3/7, 8 and 9 levels. WPE1-NA22, BPH-1, LNCaP, and VCaP cell viability was not affected by treatment with the GnRH agonists leuprolide and goserelin. Using MALDI MS, we detected changes in m/z signals that were robust enough to create a complete discriminatory profile induced by degarelix. Transcriptomic analysis of BPH-1 cells provided a global map of genes affected by degarelix and indicated that the biological processes affected were related to cell growth, G-coupled receptors, the mitogen-activated protein kinase (MAPK) pathway, angiogenesis and cell adhesion. Taken together, these data demonstrate that (i) the GnRH antagonist degarelix exerts a direct effect on prostate cell growth through apoptosis; (ii) MALDI MS analysis provided a basis to fingerprint degarelix-treated prostate cells; and (iii) the clusters of genes affected by degarelix suggest that this compound, in addition to its known use in the treatment of prostate cancer, may be efficacious in BPH.
Highlights
Gonadotropin-releasing hormone (GnRH) antagonists are a new class of pharmacological treatment with many potential applications [1,2,3,4]
Considering the interest of the work on the mechanism of action of degarelix in vitro, we investigated the expression of GNRH endogenous ligands, GNRHR, and their isoforms
GNRHR1 was present at low levels in benign prostatic hyperplasia (BPH)-1 cells, whereas it was expressed at high levels in WPE1-NA22 cells (Fig. 2B)
Summary
Gonadotropin-releasing hormone (GnRH) antagonists are a new class of pharmacological treatment with many potential applications [1,2,3,4]. Low or castrated levels of circulating testosterone are desirable since testosterone promotes prostate growth [1,3,5,6] Those low levels can be induced by using GnRH antagonists or agonists. GnRH antagonists (such as degarelix) compete with the endogenous hypothalamic ligand GnRH to bind to the GnRH receptor (GnRHR) In men, this blockage leads to a decrease in both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release from the pituitary, and subsequently testosterone production from testes is suppressed. Before inducing low testosterone levels, GnRH agonists promote an initial stimulation of the HPG axis, causing an undesirable surge of testosterone that risks enhancement of steroid-dependent disease symptoms, or it may result in a clinical flare [7,8,9,10,11]. Antagonists provide an immediate onset of action; in addition, no testosterone levels surge and efficient action can be reversed or sustained upon repeated dosing [4,12]
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