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Proc Natl Acad Sci U S A. 2019 Feb 5;116(6):2226-2231. doi: 10.1073/pnas.1818865116. Epub 2019 Jan 18.

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

Author information

1
Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, Italy.
2
Department of Medical Sciences, University of Turin, 10126 Turin, Italy.
3
Italian Institute for Genomic Medicine, 10126 Turin, Italy.
4
Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy.
5
Department of Oncology, University of Turin, 10126 Turin, Italy.
6
Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, 10043 Orbassano, Italy.
7
Pathology Unit, SS. Antonio e Biagio General Hospital, 15121 Alessandria, Italy.
8
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136.
9
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125.
10
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136; andrew.schally@va.gov riccarda.granata@unito.it.
11
Sylvester Comprehensive Cancer Center, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136.
12
Division of Hematology/Oncology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136.
13
Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136.
14
Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, Italy; andrew.schally@va.gov riccarda.granata@unito.it.

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.

KEYWORDS:

GHRH antagonists; GHRH receptor; growth hormone-releasing hormone; malignant pleural mesothelioma

Conflict of interest statement

Conflict of interest statement: A.V.S. and R.C. are listed as co-inventors on the patent for GHRH agonists, assigned to the University of Miami, Miami, FL, and the Veterans Affairs Medical Center, Miami, FL. The remaining authors declare no conflict of interest.

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