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

Tania Villanova, Iacopo Gesmundo, Valentina Audrito, Nicoletta Vitale, Francesca Silvagno, Chiara Musuraca, Luisella Righi, Roberta Libener, Chiara Riganti, Paolo Bironzo, Silvia Deaglio, Mauro Papotti, Renzhi Cai, Wei Sha, Ezio Ghigo, Andrew V Schally, Riccarda Granata

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2226-2231
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number6
DOIs
StatePublished - Feb 5 2019

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Growth Hormone-Releasing Hormone
Hormone Antagonists
Growth
Heterografts
Pemetrexed
Lung Neoplasms
Malignant Mesothelioma
Drug Therapy
Cell Line
Asbestos
Matrix Metalloproteinases
Insulin-Like Growth Factor I
Vascular Endothelial Growth Factor A
Cell Movement
Reactive Oxygen Species
Neoplasms
Therapeutics

Keywords

  • GHRH antagonists
  • GHRH receptor
  • Growth hormone-releasing hormone
  • Malignant pleural mesothelioma

ASJC Scopus subject areas

  • General

Cite this

Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of human malignant pleural mesothelioma. / Villanova, Tania; Gesmundo, Iacopo; Audrito, Valentina; Vitale, Nicoletta; Silvagno, Francesca; Musuraca, Chiara; Righi, Luisella; Libener, Roberta; Riganti, Chiara; Bironzo, Paolo; Deaglio, Silvia; Papotti, Mauro; Cai, Renzhi; Sha, Wei; Ghigo, Ezio; Schally, Andrew V; Granata, Riccarda.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 6, 05.02.2019, p. 2226-2231.

Research output: Contribution to journalArticle

Villanova, T, Gesmundo, I, Audrito, V, Vitale, N, Silvagno, F, Musuraca, C, Righi, L, Libener, R, Riganti, C, Bironzo, P, Deaglio, S, Papotti, M, Cai, R, Sha, W, Ghigo, E, Schally, AV & Granata, R 2019, 'Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of human malignant pleural mesothelioma', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 6, pp. 2226-2231. https://doi.org/10.1073/pnas.1818865116
Villanova, Tania ; Gesmundo, Iacopo ; Audrito, Valentina ; Vitale, Nicoletta ; Silvagno, Francesca ; Musuraca, Chiara ; Righi, Luisella ; Libener, Roberta ; Riganti, Chiara ; Bironzo, Paolo ; Deaglio, Silvia ; Papotti, Mauro ; Cai, Renzhi ; Sha, Wei ; Ghigo, Ezio ; Schally, Andrew V ; Granata, Riccarda. / Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of human malignant pleural mesothelioma. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 6. pp. 2226-2231.
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AU - Villanova, Tania

AU - Gesmundo, Iacopo

AU - Audrito, Valentina

AU - Vitale, Nicoletta

AU - Silvagno, Francesca

AU - Musuraca, Chiara

AU - Righi, Luisella

AU - Libener, Roberta

AU - Riganti, Chiara

AU - Bironzo, Paolo

AU - Deaglio, Silvia

AU - Papotti, Mauro

AU - Cai, Renzhi

AU - Sha, Wei

AU - Ghigo, Ezio

AU - Schally, Andrew V

AU - Granata, Riccarda

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N2 - 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.

AB - 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.

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