Antagonists of growth hormone-releasing hormone (GHRH) reduce prostate size in experimental benign prostatic hyperplasia
- 14 February 2011
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 108 (9), 3755-3760
- https://doi.org/10.1073/pnas.1018086108
Abstract
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.Keywords
This publication has 40 references indexed in Scilit:
- A role for epithelial-mesenchymal transition in the etiology of benign prostatic hyperplasiaProceedings of the National Academy of Sciences of the United States of America, 2009
- Il‐1β‐induced post‐transition effect of NF‐kappaB provides time‐dependent wave of signals for initial phase of intrapostatic inflammationThe Prostate, 2009
- Antioxidant activity of growth hormone-releasing hormone antagonists in LNCaP human prostate cancer lineProceedings of the National Academy of Sciences of the United States of America, 2008
- Prostatic stromal cells derived from benign prostatic hyperplasia specimens possess stem cell like propertyThe Prostate, 2007
- Potentiation of mammary cancer inhibition by combination of antagonists of growth hormone-releasing hormone with docetaxelProceedings of the National Academy of Sciences of the United States of America, 2007
- Immunocytochemical localisation of plasma membrane GHRH receptors in human tumours using a novel anti-peptide antibodyEuropean Journal Of Cancer, 2006
- Synergistic inhibition of growth of lung carcinomas by antagonists of growth hormone-releasing hormone in combination with docetaxelProceedings of the National Academy of Sciences of the United States of America, 2006
- Benign prostatic hyperplasia: age-related tissue-remodelingExperimental Gerontology, 2005
- Suppression of growth of H‐69 small cell lung carcinoma by antagonists of growth hormone releasing hormone and bombesin is associated with an inhibition of protein kinase C signalingInternational Journal of Cancer, 2004
- Increased growth factor production in a human prostatic stromal cell culture model caused by hypoxiaThe Prostate, 2003