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.

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;Righi, Luisella;Riganti, Chiara;Bironzo, Paolo;Deaglio, Silvia;Papotti, Mauro;Ghigo, Ezio;Granata, Riccarda
Last
2019

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.
116
6
2226
2231
https://www.pnas.org/content/early/2019/01/17/1818865116
GHRH antagonists; GHRH receptor; growth hormone-releasing hormone; 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
File in questo prodotto:
File Dimensione Formato  
VILLANOVA GHRH ANTAGONISTS MESOTHELIOMA PNAS 2019.pdf

Accesso aperto

Tipo di file: PDF EDITORIALE
Dimensione 1 MB
Formato Adobe PDF
1 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1690097
Citazioni
  • ???jsp.display-item.citation.pmc??? 14
  • Scopus 20
  • ???jsp.display-item.citation.isi??? 21
social impact