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Mechanisms of synergism between antagonists of growth hormone‐releasing hormone and antagonists of luteinizing hormone‐releasing hormone in shrinking experimental benign prostatic hyperplasia
Author(s) -
Rick Ferenc G.,
Schally Andrew V.,
Block Norman L.,
AbiChaker Andrew,
Krishan Awtar,
Szalontay Luca
Publication year - 2013
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.22633
Subject(s) - endocrinology , medicine , luteinizing hormone , hyperplasia , prostate , stromal cell , testosterone (patch) , antagonist , prostate cancer , growth hormone–releasing hormone , hormone , receptor , cancer , growth hormone
BACKGROUND 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. METHODS 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. RESULTS 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 G 0 /G 1 and G 2 /M DNA content. Significant changes in expression of >40 gene transcripts related to growth factors, inflammatory cytokines, and signal transduction were identified. CONCLUSIONS 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. Prostate 73: 873–883, 2013. © 2012 Wiley Periodicals, Inc.