Antagonists of growth hormone-releasing hormone (GHRH) reduce prostate size in experimental benign prostatic hyperplasia

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. chronic prostatic inflammation | prostatic hypertrophy | prostatic cell death | rodent benign prostatic hyperplasia model T he hypothalamic neuropeptide growth hormone-releasing hormone (GHRH) stimulates the secretion of growth hormone (GH) from the anterior pituitary gland upon binding to its receptor (GHRH-R) (1). In turn, GH stimulates the production of insulin-like growth factor 1 (IGF1), a major anabolic growth factor and a potent mitogen for many cancers (2). GHRH and its pituitary-type receptor as well as its truncated receptor splice variants (SV) are expressed in various normal human tissues including prostate, kidney, lung, and liver (3) and on many human cancer cell lines and tumors (1). Pituitary-type GHRH-R and SV1 appear to mediate effects of GHRH and its antagonists on tumors (4). GHRH itself acts as an autocrine/paracrine growth factor in human cancers (1, 5), including prostate (6).To develop therapies for cancer, our laboratory has synthesized GHRH antagonists with high antiproliferative activity in numerous experimental cancer models (1). The inhibitory effect of these analogs is exerted in part by indirect endocrine mechanisms through the suppression of GHRH-evoked release of GH from the pituitary, which in turn results in the inhibition of the hepatic production of...

Antagonists of growth hormone-releasing hormone inhibit growth of androgen-independent prostate cancer through inactivation of ERK and Akt kinases

“…Our observation of the transcriptional suppression of Cdkn1a/p21 and Cdkn2a/p16, factors involved in cell-cycle control and DNA damage repair, in PC-3 tumors after treatment with the GHRH antagonist JMR-132 are in line with our recent findings (17). The mRNA levels of the proapoptotic genes Bad and Bax were up-regulated, whereas the expression of antiapoptotic Bcl2 was lowered significantly, confirming our recent observations (28,47). We found that transcriptional levels of signal transduction molecules and transcription factors Akt1, Erbb2, Fas, and Nfkb1 were down-regulated after treatment with JMR-132.…”

“…Specific, high-affinity binding sites for GHRH also were demonstrated by radioligand assays in 60% of prostate cancer specimens (27). Furthermore, the expression of pituitarytype GHRH-R in normal human (8) and rat (28) prostates was reported recently. It appears that SV1 is the predominant type of GHRH-R on certain cancer cells or tumors (6,16,28).…”

“…Furthermore, the expression of pituitarytype GHRH-R in normal human (8) and rat (28) prostates was reported recently. It appears that SV1 is the predominant type of GHRH-R on certain cancer cells or tumors (6,16,28). Thus, SV1-type GHRH receptors could function as the main therapeutic target for the anticancer effect of GHRH antagonists.…”

Antagonists of growth hormone releasing hormone (GHRH) given before whole body radiation lead to modulation of radiation response and organ-specific changes in the expression of angiogenesis

“…The finding that GHRH can function as a tumor growth factor [5][6][7][8][9][12][13][14][15][16] increased interest in the development of GHRH antagonists. Antagonists of GHRH can exert both direct and indirect effects on tumors and other tissues.…”

“…Quantitative mRNA expression analysis of 84 genes representative of the major biological pathways involved in transformation and tumorigenesis was performed with the Mouse Cancer PathwayFinder™ RT 2 Profiler™ PCR Array (SABioscience Corporation, Frederick, MD). The yield and the quality of RNA samples, synthesis of cDNA, and real-time RT-PCT arrays were performed as described [14]. Real-time PCR reactions were performed in the iCycler iQ™ Real-Time PCR Detection System (Bio-Rad, Hercules, CA).…”