Journal Article

Shrinkage of experimental benign prostatic hyperplasia and reduction of prostatic cell volume by a gastrin-releasing peptide antagonist

Shamaladevi, Nagarajarao, Vidaurre, Irving, Schally, Andrew V., Szalontay, Luca, Jaszberenyi, Miklos, Szepeshazi, Karoly, Block, Norman L., Abi-Chaker, Andrew, Jayakumar, Arumugam R., Halmos, Gabor, Perez, Roberto, Rick, Ferenc G., Krishan, Awtar

2013

Overview

Gastrin releasing-peptide (GRP) is a potent growth factor in many malignancies. Benign prostatic hyperplasia (BPH) is a progressive age-related proliferation of glandular and stromal tissues; various growth factors and inflammatory processes are involved in its pathogenesis. We have demonstrated that potent antagonists of GRP inhibit growth of experimental human tumors including prostate cancer, but their effect on models of BPH has not been studied. Here, we evaluated the effects of GRP antagonist RC-3940-II on viability and cell volume of BPH-1 human prostate epithelial cells and WPMY-1 prostate stromal cells in vitro, and in testosterone-induced BPH in Wistar rats in vivo. RC-3940-II inhibited the proliferation of BPH-1 and WPMY-1 cells in a dose-dependent manner and reduced prostatic cell volume in vitro. Shrinkage of prostates was observed after 6 wk of treatment with RC-3940-II: a 15.9% decline with 25 μg/d; and a 18.4% reduction with 50 μg/d (P < 0.05 for all). Significant reduction in levels of proliferating cell nuclear antigen, NF-κβ/p50, cyclooxygenase-2, and androgen receptor was also seen. Analysis of transcript levels of genes related to growth, inflammatory processes, and signal transduction showed significant changes in the expression of more than 90 genes (P < 0.05). In conclusion, GRP antagonists reduce volume of human prostatic cells and lower prostate weight in experimental BPH through direct inhibitory effects on prostatic GRP receptors. GRP antagonists should be considered for further development as therapy for BPH.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Analysis of Variance / androgen receptors / Animals / antagonists / Apoptosis - drug effects / Biological Sciences / Blotting, Western / Bombesin - analogs & derivatives / Bombesin - pharmacology / Cell cycle / Cell growth / Cell Line / Cell lines / Cell Proliferation - drug effects / Cell Size - drug effects / cell viability / Cells / Cyclooxygenase 2 - blood / dose response / Dose-Response Relationship, Drug / Epithelial cells / gastrin-releasing peptide / Gastrin-Releasing Peptide - antagonists & inhibitors / Gene Expression Profiling / genes / Growth factors / Human growth / Humans / hyperplasia / Male / NF-kappa B - blood / pathogenesis / Peptide Fragments - pharmacology / Peptides / proliferating cell nuclear antigen / Proliferating Cell Nuclear Antigen - blood / prostaglandin synthase / Prostate / Prostate - cytology / Prostate - drug effects / Prostate cancer / prostate gland / Prostatic hyperplasia / Prostatic Hyperplasia - chemically induced / Prostatic Hyperplasia - drug therapy / prostatic neoplasms / Rats / Real-Time Polymerase Chain Reaction / Receptors / Receptors, Androgen - blood / Reverse Transcriptase Polymerase Chain Reaction / Rodents / shrinkage / Signal transduction / Stromal cells / Testosterone - toxicity / Tetrazolium Salts / therapeutics / Thiazoles