Pleural mesothelioma (PM) is an aggressive cancer with poor prognosis and no effective therapies, mainly caused by exposure to asbestos. Antagonists of growth hormone-releasing hormone (GHRH) display strong antitumor effects in many experimental cancers, including lung cancer and mesothelioma. Here, we aimed to determine whether GHRH antagonist MIA-690 potentiates the antitumor effect of cisplatin and pemetrexed in PM. In vitro, MIA-690, in combination with cisplatin and pemetrexed, synergistically reduced cell viability, restrained cell proliferation and enhanced apoptosis, compared with drugs alone. In vivo, the same combination resulted in a strong growth inhibition of MSTO-211H xenografts, decreased tumor cell proliferation and increased apoptosis. Mechanistically, MIA-690, particularly with chemotherapeutic drugs, inhibited proliferative and oncogenic pathways, such as MAPK ERK1/2 and cMyc, and downregulated cyclin D1 and B1 mRNAs. Inflammatory pathways such as NF-kB and STAT3 were also reduced, as well as oxidative, angiogenic and tumorigenic markers (iNOS, COX-2, MMP2, MMP9 and HMGB1) and growth factors (VEGF and IGF-1). Overall, these findings strongly suggest that GHRH antagonists of MIA class, such as MIA-690, could increase the efficacy of standard therapy in PM.

Antagonist of Growth Hormone-Releasing Hormone Potentiates the Antitumor Effect of Pemetrexed and Cisplatin in Pleural Mesothelioma

Gesmundo, Iacopo;Pedrolli, Francesca;Vitale, Nicoletta;Bertoldo, Alessia;Banfi, Dana;Granato, Giuseppina;Kasarla, Ramesh;Balzola, Federico;Deaglio, Silvia;Papotti, Mauro;Ghigo, Ezio;Granata, Riccarda
2022-01-01

Abstract

Pleural mesothelioma (PM) is an aggressive cancer with poor prognosis and no effective therapies, mainly caused by exposure to asbestos. Antagonists of growth hormone-releasing hormone (GHRH) display strong antitumor effects in many experimental cancers, including lung cancer and mesothelioma. Here, we aimed to determine whether GHRH antagonist MIA-690 potentiates the antitumor effect of cisplatin and pemetrexed in PM. In vitro, MIA-690, in combination with cisplatin and pemetrexed, synergistically reduced cell viability, restrained cell proliferation and enhanced apoptosis, compared with drugs alone. In vivo, the same combination resulted in a strong growth inhibition of MSTO-211H xenografts, decreased tumor cell proliferation and increased apoptosis. Mechanistically, MIA-690, particularly with chemotherapeutic drugs, inhibited proliferative and oncogenic pathways, such as MAPK ERK1/2 and cMyc, and downregulated cyclin D1 and B1 mRNAs. Inflammatory pathways such as NF-kB and STAT3 were also reduced, as well as oxidative, angiogenic and tumorigenic markers (iNOS, COX-2, MMP2, MMP9 and HMGB1) and growth factors (VEGF and IGF-1). Overall, these findings strongly suggest that GHRH antagonists of MIA class, such as MIA-690, could increase the efficacy of standard therapy in PM.
2022
23
19
1
16
https://www.mdpi.com/1422-0067/23/19/11248
GHRH antagonists; chemotherapeutic drugs; pleural mesothelioma; Cell Line, Tumor; Cisplatin; Cyclin D1; Cyclooxygenase 2; Growth Hormone-Releasing Hormone; Humans; Insulin-Like Growth Factor I; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; NF-kappa B; Pemetrexed; Vascular Endothelial Growth Factor A; HMGB1 Protein; Mesothelioma; Mesothelioma, Malignant; Pleural Neoplasms
Gesmundo, Iacopo; Pedrolli, Francesca; Vitale, Nicoletta; Bertoldo, Alessia; Orlando, Giulia; Banfi, Dana; Granato, Giuseppina; Kasarla, Ramesh; Balzola, Federico; Deaglio, Silvia; Cai, Renzhi; Sha, Wei; Papotti, Mauro; Ghigo, Ezio; Schally, Andrew V; Granata, Riccarda
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1881601
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