In Search of the Molecular Mechanisms Mediating the Inhibitory Effect of the GnRH Antagonist Degarelix on Human Prostate Cell Growth

Sakai, Mônica; Martinez–Arguelles, Daniel B.; Patterson, Nathan Heath; Chaurand, Pierre; Papadopoulos, Vassilios

doi:10.1371/journal.pone.0120670

Cited by 22 publications

(24 citation statements)

References 61 publications

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“…Thus, results that were observed for primary BPH cells in this study seem to be specific for the antagonist degarelix. In agreement with recent studies showing a direct inhibitory effect of degarelix on human prostate cell lines growth attributed to increased apoptosis [48], the inhibitory effects of degarelix on primary BPH cell growth is likely mediated by increased caspase 3/7 levels inducing apoptosis.…”

supporting

confidence: 91%

“…We recently reported that degarelix exerts a direct effect on human prostate cell lines including normal prostate myofibroblast WPMY-1 and epithelial WPE1-NA22 cells, benign prostatic hyperplasia (BPH)-1 cells, androgen-dependent LNCaP prostate cancer cells, and VCaP cells derived from a patient with castration-resistant prostate cancer [48]. The results obtained with the primary BPH cells point to the same general observation with respect to the biological response to degarelix: the inhibition of cell growth.…”

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confidence: 99%

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The GnRH Antagonist Degarelix Directly Inhibits Benign Prostate Hyperplasia Cell Growth

2015

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Gonadotropin-releasing hormone receptors (GnRHR) have been found in extrapituitary tissues, including the prostate, where they might exert a local effect on tissue growth. Degarelix is a GnRHR antagonist approved for use in patients with prostate cancer (PCa) who need androgen deprivation therapy. The slowing of prostate cell growth is a common goal shared by PCa and benign prostate hyperplasia (BPH) patients, and the effect of degarelix on BPH cells has not yet been investigated. We wanted to evaluate the direct effect of degarelix on human BPH primary cell growth. Gene expression studies performed with BPH (n=11), stage 0 (n=15), and PCa (n=65) human specimens demonstrated the presence of GNRHR1 and GNRHR2 and their respective endogenous peptide ligands. BPH-isolated epithelial and stromal cells were either cultured alone or co-cultured (1:4 or 4:1 ratio of epithelial to stromal cells) and subsequently treated with increasing concentrations of degarelix. Degarelix treatment induced a decrease in cell viability and cell proliferation rates, which occurred in parallel to an increase in apoptosis. Both epithelial and stromal BPH cells are sensitive to degarelix treatment and, interestingly, degarelix is also effective when the cells were growing in a co-culture microenvironment. In contrast to degarelix, the GnRHR agonists, leuprolide and goserelin, exerted no effect on the viability of BPH epithelial or stromal cells. In conclusion, (i) prostate tissues express GNRHR and are a potential target for degarelix; and (ii) degarelix directly inhibits BPH cell growth through a decrease in cell proliferation and an increase in apoptosis. Supporting information for this article is available online at http://www.thieme-connect.de/products.

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confidence: 99%

The GnRH Antagonist Degarelix Directly Inhibits Benign Prostate Hyperplasia Cell Growth

2015

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“…Additionally, we further assessed impact of NQO1 absence on prostatic hyperplasia in other types of prostate‐related cell lines. Previously, Sakai, Martinez‐Arguelles, Patterson, Chaurand, and Papadopoulos () reported different hormone‐related gene expressions in different type of established prostate cell lines (Sakai et al., ). This was in lined with the present study.…”

Section: Discussionmentioning

confidence: 99%

NAD(P)H-quinone oxidoreductase 1 silencing aggravates hormone-induced prostatic hyperplasia in mice

Kim

Park

et al. 2017

Andrologia

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NAD(P)H-quinone oxidoreductase 1 (NQO1) is a highly inducible flavoprotein known to involve in various cellular defence mechanisms. In this study, we explored whether NQO1 deletion affects hormone-induced prostatic hyperplasia. Testosterone propionate (3 mg/kg, IP) was injected into wild-type (WT) and NOQ1 knockout C57BL/6 mice (NQO1 ) for 14 consecutive days, and the samples were collected for biological and histochemical studies. The testosterone-treated NQO1 showed about 140% higher prostate weight than the testosterone-treated WT, with enhanced connective tissue and hyperplastic glands formations. However, increased dihydrotestosterone level after testosterone treatment was not significantly different between the WT and NQO1 . In contrast, the enhanced nuclear expression of proliferating cell nuclear antigen in NQO1 prostate confirmed aggravated prostatic hyperplasia in NQO1 . Moreover, the expression of heat shock protein (HSP) 90-α was markedly increased in the NQO1 , and this was supported by increased testosterone-induced nuclear androgen receptor expression in NQO1-silenced LNCaP cells. Testosterone-induced prostate-specific antigen expression was not reversed in NOQ1-silenced cells after finasteride treatment. Although the exact role of NQO1 in prostatic hyperplasia remains unclear, the hyperplasia exacerbation due to NQO1 deletion might be independent of type 2 5α-reductase and might be related to enhanced androgen receptor affinity due to enhanced HSP90-α expression.

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“…It is only known that leukotriene B4 receptor antagonist can cause inhibition of the ovulation in rats [13], that the administration of leukotriene D4 antagonists' results in lack of progression to the luteal phase of the estrous cycle [14] and that corpus luteum produced leukotriene B4 inversely correlated with the secretion rates of progesterone [7]. Furthermore, GnRH antagonist may act on various pathways by inhibiting MAPK [15] or by inducing apoptosis [16] and nitric oxide synthesis [17], explaining potential effects on OHSS. Finally, Heparin, which controls the risk of thrombosis, blastocyst apposition, adherence and implantation as well as trophoblast differentiation and invasion [18], caused a slight reduction in the vascular permeability in our experiments.…”

Section: Discussionmentioning

confidence: 99%

The combination of Everolimus with Verapamil reduces ovarian weight and vascular permeability on ovarian hyperstimulation syndrome: a preclinical experimental randomized controlled study

Kitsou

Kosmas

Lazaros

et al. 2016

Gynecological Endocrinology

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The efficacy of pathways inhibition and the combined effect of Everolimus (mTOR inhibitor) and Verapamil (CYP3A inhibitor) in ovarian hyperstimulation syndrome (OHSS) need to be tested. Therefore, the impact of a leucotriene receptor antagonist, an anticoagulant, a GnRH antagonist as well as Everolimus plus Verapamil (at various doses and days of administration) on an OHSS rat model was tested. Sixty three female Wistar rats were randomly divided into seven groups. The control group received saline, while the OHSS group received rec-FSH for four consecutive days. The other five groups received rec-FSH for four days and Montelukast daily, Heparin daily, GnRH antagonist daily, Everolimus plus Verapamil in the last two days (half days group) and Everolimus plus Verapamil (half dose group) daily, respectively. All groups received also hCG at the fifth day. Significantly reduced ovarian weight was observed in the Everolimus plus Verapamil groups (half days and half-dose groups) and the Montelukast group compared to the OHSS group (p = 0.001 and p = 0.001, respectively). The vascular permeability was significantly reduced in the Everolimus plus Verapamil group (half dose group) and the GnRH antagonist group compared to the OHSS group (p< 0.001 and p = 0.011, respectively). However, estradiol and progesterone levels did not differ significantly between the groups. Studying the inhibition of different pathways, we concluded that the co-administration of Everolimus and Verapamil (at half dose) is beneficial for reducing ovarian weight and vascular permeability in an OHSS animal model.

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In Search of the Molecular Mechanisms Mediating the Inhibitory Effect of the GnRH Antagonist Degarelix on Human Prostate Cell Growth

Cited by 22 publications

References 61 publications

The GnRH Antagonist Degarelix Directly Inhibits Benign Prostate Hyperplasia Cell Growth

The GnRH Antagonist Degarelix Directly Inhibits Benign Prostate Hyperplasia Cell Growth

NAD(P)H-quinone oxidoreductase 1 silencing aggravates hormone-induced prostatic hyperplasia in mice

The combination of Everolimus with Verapamil reduces ovarian weight and vascular permeability on ovarian hyperstimulation syndrome: a preclinical experimental randomized controlled study

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