Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of human malignant pleural mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated with exposure to asbestos, with poor prognosis and no effective therapies. The strong inhibitory activities of growth hormone-releasing hormone (GHRH) antagonists have been demonstrated in different experimental human cancers, including lung cancer; however, their role in MPM remains unknown. We assessed the effects of the GHRH antagonists MIA-602 and MIA-690 in vitro in MPM cell lines and in primary MPM cells, and in vivo in MPM xenografts. GHRH, GHRH receptor, and its main splice variant SV1 were found in all the MPM cell types examined. In vitro, MIA-602 and MIA-690 reduced survival and proliferation in both MPM cell lines and primary cells and showed synergistic inhibitory activity with the chemotherapy drug pemetrexed. In MPM cells, GHRH antagonists also regulated activity and expression of apoptotic molecules, inhibited cell migration, and reduced the expression of matrix metalloproteinases. These effects were accompanied by impairment of mitochondrial activity and increased production of reactive oxygen species. In vivo, s.c. administration of MIA-602 and MIA-690 at the dose of 5 μg/d for 4 wk strongly inhibited the growth of MPM xenografts in mice, along with reduction of tumor insulin-like growth factor-I and vascular endothelial growth factor. Overall, these results suggest that treatment with GHRH antagonists, alone or in association with chemotherapy, may offer an approach for the treatment of MPM.

Antinflammatory, antioxidant, and behavioral effects induced by administration of growth hormone-releasing hormone analogs in mice

“…In vivo studies. After 2-week acclimation, mice were randomized into three groups and treated daily for 4 weeks by subcutaneous administration of GHRH antagonist MIA 690 (5 μg), GHRH agonist MR 409 (5 μg) or vehicle solution 18 . All solutions were prepared freshly before use.The doses were selected based on previous studies including oncology.…”

“…All solutions were prepared freshly before use.The doses were selected based on previous studies including oncology. Injection volume was 0.1 ml for s.c. injection 16,18 . The animals were brought into the experimental room 30 min prior to the test in order to acclimate to the environment, and were kept in the testing chamber for 5 min prior to each test.…”

“…Blots were reprobed with actin (dilution 1:500, mouse monoclonal actin antibody, Santa Cruz Biotechnology, sc-376421) for protein normalization. Immunoreactive proteins were visualized using horseradish peroxidase-conjugated goat anti-mouse, goat anti-rabbit or mouse anti-goat (1:4000) secondary antibodies by enhanced chemiluminescence substrate (ECL) using ChemiDoc XRS (Bio-Rad), densitometric analysis was performed with Quantity One software (Bio-Rad) 18 .…”

GHRH antagonists support lung endothelial barrier function

“…The biological activity of GHRH is retained in the first 29 amino acids [GHRH (1-29) NH 2 ]. 1,2 Antagonists of GHRH exert powerful anticancer and antiinflammatory activities. 3 Those compounds could provide therapeutic approaches toward malignancies, since they "target" tumor cells and reduce their growth under experimental conditions "in vivo" and "in vitro".…”

Splice variant of growth hormone-releasing hormone receptor drives esophageal squamous cell carcinoma conferring a therapeutic target

“…A stimulatory loop formed by tumor-derived growth hormonereleasing hormone (GHRH) and its receptors has been shown to promote the growth of many cancers, which can be blocked by antagonists of GHRH's cognate receptor (GHRH-R) (8)(9)(10). Thus, the pituitary-type GHRH receptor (pGHRH-R), a canonical fulllength transcript, has been detected in many human neoplastic cells and tissues, mediating the antiproliferative effects of GHRH-R antagonists (8,9,(11)(12)(13)(14).…”