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

Our plain-English summary of Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of human malignant pleural mesothelioma, by T. Villanova, I. Gesmundo, V. Audrito, et al (Proceedings of the National Academy of Sciences of the United States of America, 2019).

The study

• Authors: T. Villanova, I. Gesmundo, V. Audrito, N. Vitale, F. Silvagno, C. Musuraca, L. Righi, R. Libener, C. Riganti, P. Bironzo, S. Deaglio, M. Papotti, R. Cai, W. Sha, E. Ghigo, A.V. Schally, R. Granata
• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Published: 2019;116(6):2226-2231
• Cited by: 35 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

Copyright © 2019 the Author(s). Published by PNAS.

In plain English

This was a laboratory and animal study; no patients were treated. The authors tested two experimental compounds, MIA-602 and MIA-690, which block growth hormone-releasing hormone (GHRH), on malignant pleural mesothelioma cells. They used two mesothelioma cell lines (MSTO-211H, biphasic, and REN, epithelioid), non-cancerous pleural mesothelial cells (MeT-5A), and biphasic, epithelioid and sarcomatoid cells taken from patients' diagnostic biopsies. All of these cells contained GHRH and its receptors. In the dish, both compounds reduced survival and growth of the mesothelioma cells as the dose increased. In the two mesothelioma cell lines, they also acted synergistically with the chemotherapy drug pemetrexed in reducing cell survival, raised markers of cell death, slowed cell migration and impaired mitochondria. In the non-cancerous MeT-5A cells they reduced survival only at the highest concentrations and did not affect growth. In mice carrying MSTO-211H tumors (15 per group), a daily injection of 5 micrograms for 4 weeks reduced tumor volume and weight compared with mice given an inactive vehicle (P less than 0.001). The authors concluded that the compounds could be considered for future mesothelioma treatment, alone or with standard therapies.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) experiments on cell lines and patient-derived cells, plus an animal experiment in mice implanted with human mesothelioma cells (xenografts)
• Who was studied: Human mesothelioma cell lines MSTO-211H (biphasic) and REN (epithelioid); non-cancerous MeT-5A pleural mesothelial cells; primary biphasic, epithelioid and sarcomatoid mesothelioma cells from diagnostic thoracoscopies of patients in Italy (number of patients not stated); 6- to 8-week-old male immunodeficient (NOD/SCID/gamma chain knockout) mice, 15 per group
• Exposure: Not an asbestos exposure study. The exposure was treatment with the GHRH antagonists MIA-602 and MIA-690: 1 to 2,000 nM in cells (1 µM in most experiments), alone or with pemetrexed; in mice, 5 µg per day by injection under the skin for 4 weeks, compared with vehicle
• Main results:
  • GHRH receptor (pGHRH-R), its splice variant SV1, and GHRH protein were found in MeT-5A cells and in both mesothelioma cell lines
  • In the mesothelioma cell lines, survival and proliferation fell as the dose increased. IC50 for MIA-602 was 3,925 nM in MSTO-211H and 2,350 nM in REN. IC50 for MIA-690 was 2,779 nM in MSTO-211H and 2,431 nM in REN
  • In non-cancerous MeT-5A pleural mesothelial cells, both compounds reduced survival only at the highest concentrations and had no effect on proliferation
  • Combined with pemetrexed, both compounds were synergistic in reducing survival of both mesothelioma cell lines (Combination Index below 1 at all pemetrexed concentrations tested)
  • In both mesothelioma cell lines, both compounds increased caspase-3 activity (a cell-death marker) at 24 hours
  • Both compounds strongly inhibited wound closure (cell migration) in both mesothelioma cell lines
  • Mitochondrial membrane potential was reduced in both mesothelioma cell lines after 48 hours of treatment
  • In primary cells from patients, both compounds reduced survival and proliferation of biphasic, epithelioid and sarcomatoid mesothelioma cells as the dose increased
  • In mice with MSTO-211H tumors (n = 15 per group), both compounds reduced tumor volume and weight compared with vehicle (P less than 0.001)
  • In the mouse tumors, the compounds reduced IGF-I protein and VEGF mRNA levels
  • Mean tumor necrosis was slightly higher in treated mice: 35% with MIA-602 and 36% with MIA-690, compared with 29% in untreated xenografts
• The authors' conclusion: The authors concluded that their results show antitumor activity of MIA-602 and MIA-690 in mesothelioma in vitro and in vivo, and that GHRH antagonists could be considered for future treatment strategies, alone or combined with standard therapies

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Prognosis, Lung Cancer, Chemotherapy, Pemetrexed (Alimta), Reactive Oxygen Species (ROS).

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