sermorelin and Prostatic-Hyperplasia

Benign prostatic hyperplasia (BPH) affects aging men. Combined therapy with antagonists of growth hormone-releasing hormone (GHRH) and of luteinizing hormone-releasing hormone (LHRH or GnRH) induces prostate shrinkage in rat models. We investigated the mechanisms of action of this combination on cell cycle traverse and expression of prostatic genes.. Effects of GHRH antagonist, JMR-132 (40 µg/day), the LHRH antagonist, cetrorelix (0.625 mg/kg), and their combination were evaluated on testosterone-induced benign prostatic hyperplasia in male Wistar rats. Influence of JMR-132, cetrorelix, and their combinations on cell viability was assessed by MTS assay in BPH-1 human prostate epithelial cells and WPMY-1 normal prostate stromal cells. Cell cycle was analyzed by laser flow cytometry. Real-time PCR arrays were performed.. The combination of antagonists caused marked shrinkage of rat prostate (29.5%). In vitro, JMR-132 plus cetrorelix (both 5µM) produced synergistic (57.4%) inhibition of growth of BPH-1 cells, but a lesser inhibition (46%) of WPMY-1 cells. Co-treatment of with JMR-132 plus cetrorelix induced a significant increase of BPH-1 cells blocked in S-phase plus cells with lower G0 /G1 and G2 /M DNA content. Significant changes in expression of >40 gene transcripts related to growth factors, inflammatory cytokines, and signal transduction were identified.. GHRH antagonist and LHRH antagonist combination potentiates rat prostate weight reduction and synergistically inhibits of growth of BPH-1 leading to cell cycle arrest in S-phase. These effects were lesser in normal stromal prostate cell line, WPMY-1. Our findings suggest that GHRH antagonists could be useful for BPH therapy, possibly in combination with LHRH antagonists.

Topics: Animals; Cell Cycle Checkpoints; Cell Line; Cell Survival; Down-Regulation; Drug Synergism; Gene Expression Profiling; Gonadotropin-Releasing Hormone; Growth Hormone-Releasing Hormone; Humans; Male; Organ Size; Prostatic Hyperplasia; Rats; Rats, Wistar; Sermorelin; Signal Transduction

Benign prostatic hyperplasia often affects aging men. Antagonists of the neuropeptide growth hormone-releasing hormone reduced prostate weight in an androgen induced benign prostatic hyperplasia model in rats. Luteinizing hormone-releasing hormone antagonists also produce marked, protracted improvement in lower urinary tract symptoms, reduced prostate volume and an increased urinary peak flow rate in men with benign prostatic hyperplasia. We investigated the influence of a combination of antagonists of growth hormone-releasing hormone and luteinizing hormone-releasing hormone on animal models of benign prostatic hyperplasia.. We evaluated the effects of the growth hormone-releasing hormone antagonist JMR-132, given at a dose of 40 μg daily, the luteinizing hormone-releasing hormone antagonist cetrorelix, given at a dose of 0.625 mg/kg, and their combination on testosterone induced benign prostatic hyperplasia in adult male Wistar rats in vivo. Prostate tissue was examined biochemically and histologically. Serum levels of growth hormone, luteinizing hormone, insulin-like growth factor-1, dihydrotestosterone and prostate specific antigen were determined.. Marked shrinkage of the rat prostate (30.3%) occurred in response to the combination of growth hormone-releasing hormone and luteinizing hormone-releasing hormone antagonists (p<0.01). The combination strongly decreased prostatic prostate specific antigen, 6-transmembrane epithelial antigen of the prostate, interleukin-1β, nuclear factor-κβ and cyclooxygenase-2, and decreased serum prostate specific antigen.. A combination of growth hormone-releasing hormone antagonist with luteinizing hormone-releasing hormone antagonist potentiated a reduction in prostate weight in an experimental benign prostatic hyperplasia model. Results suggest that this shrinkage in prostate volume was induced by the direct inhibitory effects of growth hormone-releasing hormone and luteinizing hormone-releasing hormone antagonists exerted through their respective prostatic receptors. These findings suggest that growth hormone-releasing hormone antagonists and/or their combination with luteinizing hormone-releasing hormone antagonists should be considered for further development as therapy for benign prostatic hyperplasia.

Topics: Animals; Drug Therapy, Combination; Gonadotropin-Releasing Hormone; Growth Hormone-Releasing Hormone; Male; Organ Size; Prostatic Hyperplasia; Rats; Rats, Wistar; Sermorelin

Growth hormone-releasing hormone (GHRH), a hypothalamic polypeptide, acts as a potent autocrine/paracrine growth factor in many cancers. Benign prostatic hyperplasia (BPH) is a pathologic proliferation of prostatic glandular and stromal tissues; a variety of growth factors and inflammatory processes are inculpated in its pathogenesis. Previously we showed that potent synthetic antagonists of GHRH strongly inhibit the growth of diverse experimental human tumors including prostate cancer by suppressing various tumoral growth factors. The influence of GHRH antagonists on animal models of BPH has not been investigated. We evaluated the effects of the GHRH antagonists JMR-132 given at doses of 40 μg/d, MIA-313 at 20 μg/d, and MIA-459 at 20 μg/d in testosterone-induced BPH in Wistar rats. Reduction of prostate weights was observed after 6 wk of treatment with GHRH antagonists: a 17.8% decrease with JMR-132 treatment; a 17.0% decline with MIA-313 treatment; and a 21.4% reduction with MIA-459 treatment (P < 0.05 for all). We quantified transcript levels of genes related to growth factors, inflammatory cytokines, and signal transduction and identified significant changes in the expression of more than 80 genes (P < 0.05). Significant reductions in protein levels of IL-1β, NF-κβ/p65, and cyclooxygenase-2 (COX-2) also were observed after treatment with a GHRH antagonist. We conclude that GHRH antagonists can lower prostate weight in experimental BPH. This reduction is caused by the direct inhibitory effects of GHRH antagonists exerted through prostatic GHRH receptors. This study sheds light on the mechanism of action of GHRH antagonists in BPH and suggests that GHRH antagonists should be considered for further development as therapy for BPH.

Topics: Alternative Splicing; Animals; Apoptosis; Cell Division; Cyclooxygenase 2; Down-Regulation; Gene Expression Regulation, Neoplastic; Growth Hormone-Releasing Hormone; Humans; Immunohistochemistry; Inflammation; Inflammation Mediators; Insulin-Like Growth Factor I; Interleukin-1beta; Male; NF-kappa B; Organ Size; Prostate; Prostate-Specific Antigen; Prostatic Hyperplasia; Rats; Receptors, Androgen; Receptors, Neuropeptide; Receptors, Pituitary Hormone-Regulating Hormone; Sermorelin; Signal Transduction; Transcription, Genetic

Topics: Growth Hormone-Releasing Hormone; Humans; Male; Prostatic Hyperplasia; Sermorelin

Growth hormone-releasing hormone (GHRH), besides stimulating the secretion of GH from the pituitary gland, acts as an autocrine/paracrine growth factor in many cancers. Antagonists of GHRH inhibit growth of experimental human tumors, but their effects on benign prostatic hyperplasia (BPH) have not been studied.. We evaluated the effects of GHRH and GHRH antagonists JMR-132, MZ-5-156, MIA-601, and MIA-479 on the proliferation rate of human BPH-1 cells. We also measured by Western blot the influence of GHRH and GHRH antagonist JMR-132 on the expression of the PCNA and the activation of ERK1/2 and JAK/STAT3.. BPH-1 cells express GHRH and GHRH-receptor proteins. The proliferation rate of BPH-1 cells is increased by GHRH and inhibited by all the GHRH antagonists, the latest analogs MIA-601 and MIA-479 being the most potent. The stimulatory effect of GHRH is nullified by GHRH antagonists. GHRH strongly activates and GHRH antagonists significantly suppress the expression of the PCNA and the phosphorylation of ERK1/2 and JAK2/STAT3 pathways in these cells. Treatment with JAK2 inhibitor (AG490) decreases the proliferation rate of BPH-1 cells, and AG490 does nullify the effect of GHRH.. This study demonstrates for the first time that GHRH can act as a growth factor in BPH-1 cells and that GHRH antagonists can reverse its stimulatory effect. New observations are provided on the mechanism of action of GHRH antagonists in BPH. Our findings support the merit of further work on the development of GHRH antagonists for therapy of BPH.

Topics: Blotting, Western; Cell Line; Cell Proliferation; Enzyme Inhibitors; Growth Hormone-Releasing Hormone; HeLa Cells; Humans; Janus Kinase 2; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphorylation; Proliferating Cell Nuclear Antigen; Prostatic Hyperplasia; Sermorelin; STAT3 Transcription Factor; Tyrphostins