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

Abstract

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 dosedependent 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.bombesin | cell volume measurement | prostatic inflammation | rodent benign prostatic hyperplasia model | targeted therapy H ormonal polypeptides, bombesin (BN) and gastrin-releasing peptide (GRP), can act as autocrine and paracrine growth factors, and regulate cellular growth, differentiation, and apoptosis (1, 2). Tetradecapeptide bombesin was isolated from the skin of the European fire-bellied toad (Bombina bombina) (3), and subsequently, two mammalian bombesin-like peptides were characterized: GRP and neuromedin B (NMB) (4). GRP and BN influence the secretion of gastrointestinal hormones, stimulate the release of gastrin and somatostatin, induce pancreatic exocrine secretion (5), and induce contractions of the smooth muscle of the stomach, gall bladder, uterus, urinary bladder, and prostate (6). GRP was first shown to be a mitogen for Swiss 3T3 murine embryonal fibroblasts and, subsequently, for a number of normal cell types and cancers in vivo and in cell culture (7). GRP is now recognized as the prototypical autocrine growth factor, based on the detection of GRP and its receptors in small cell lung carcinoma and other tumors (8). GRP was shown to stimulate growth of several other types of carcinomas including those of prostate, breast, colon, and pancreas (9). Three different receptor subtypes for the BN/GRP family of peptides have been described in mammals (10). Receptor subtype 1 (termed GRP-R or BB 2 ) binds BN, GRP, and GRP antagonist RC-3940-II with high affinity (11). ...

GHRH Receptor Expression in Malignant Mixed Müllerian Tumors

“…Antagonists of GHRH-R have been demonstrated experimentally to inhibit the growth of a number of human tumors in vitro, including cancers of endometrium and ovary (9-12), prostate (23), and breast (24). The splice variant of GHRH-R has been showed to be biologically active (25), and the SV1 RNA that codes a truncated GHRH-R has been identified in human pituitary adenomas (26).…”

Personalized Medicine for the Management of Benign Prostatic Hyperplasia

“…GRP antagonists have been shown to successfully inhibit growth of numerous cancers and suppress tumor growth pathways including VEGF and FGF. 44 GRP receptor subtype 1 is expressed in human prostate tissues in normal, hyperplastic, and cancerous specimens. 45 Recently, Rick et al demonstrated that the potent GRP antagonist RC-3940-II not only inhibits prostate cancer growth but also diminishes prostate size.…”

“…45 Recently, Rick et al demonstrated that the potent GRP antagonist RC-3940-II not only inhibits prostate cancer growth but also diminishes prostate size. 44 Using a model of BPH in which rats were injected with testosterone, addition of RC-3940-II resulted in dose dependent shrinkage of prostate volume by over 15% by 6 weeks as well as decreased levels of androgen receptor and inflammatory markers. Application of this inhibitor to prostate epithelial and stromal cell lines inhibited cell proliferation and led to a decrease in levels of growth factors and proinflammatory mediators involved in BPH progression.…”

“…The reduction in prostate volume using RC-3940-II in an animal model of BPH was comparable to the size reduction with finasteride based on clinical trials, and the mechanism of action appears to be similar. 44 RC-3940-II and GRP inhibition may offer a promising new approach to BPH treatment, on its own or in combination with alpha blockers, as well as an alternative therapeutic pathway for patients who do not respond to 5AR inhibitors.…”

Activation of NF-κB Mediates Astrocyte Swelling and Brain Edema in Traumatic Brain Injury

“…Pixel volumes of these images (DAPI plus green) were quantified using the Volocity 3D Image analysis software (Volocity 6.0 High Performance 3D Cellular Imaging Software Suite; PerkinElmer) as described previously. 30,31 Values were expressed as percent change of intensity units of blue/green ratios (DAPI/NF-jB).…”