{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:48:02Z","timestamp":1787028482945,"version":"build-2736575974"},"reference-count":68,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,9,24]],"date-time":"2022-09-24T00:00:00Z","timestamp":1663977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondazione Buzzi Unicem","award":["2017HRTZYA"],"award-info":[{"award-number":["2017HRTZYA"]}]},{"name":"Fondazione Buzzi Unicem","award":["2017S55RXB_002"],"award-info":[{"award-number":["2017S55RXB_002"]}]},{"name":"Italian Ministry of Instruction and Research PRIN 2017","award":["2017HRTZYA"],"award-info":[{"award-number":["2017HRTZYA"]}]},{"name":"Italian Ministry of Instruction and Research PRIN 2017","award":["2017S55RXB_002"],"award-info":[{"award-number":["2017S55RXB_002"]}]},{"name":"Medical Research Service of the Department of Veterans Affairs","award":["2017HRTZYA"],"award-info":[{"award-number":["2017HRTZYA"]}]},{"name":"Medical Research Service of the Department of Veterans Affairs","award":["2017S55RXB_002"],"award-info":[{"award-number":["2017S55RXB_002"]}]},{"name":"University of Miami Miller School of Medicine","award":["2017HRTZYA"],"award-info":[{"award-number":["2017HRTZYA"]}]},{"name":"University of Miami Miller School of Medicine","award":["2017S55RXB_002"],"award-info":[{"award-number":["2017S55RXB_002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms231911248","type":"journal-article","created":{"date-parts":[[2022,9,25]],"date-time":"2022-09-25T23:13:27Z","timestamp":1664147607000},"page":"11248","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Antagonist of Growth Hormone-Releasing Hormone Potentiates the Antitumor Effect of Pemetrexed and Cisplatin in Pleural Mesothelioma"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4901-4764","authenticated-orcid":false,"given":"Iacopo","family":"Gesmundo","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Pedrolli","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6677-2597","authenticated-orcid":false,"given":"Nicoletta","family":"Vitale","sequence":"additional","affiliation":[{"name":"Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2798-0734","authenticated-orcid":false,"given":"Alessia","family":"Bertoldo","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Orlando","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana","family":"Banfi","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppina","family":"Granato","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9453-1106","authenticated-orcid":false,"given":"Ramesh","family":"Kasarla","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Balzola","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Azienda Ospedaliero-Universitaria Citt\u00e0 della Salute e della Scienza di Torino, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0632-5036","authenticated-orcid":false,"given":"Silvia","family":"Deaglio","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, 10126 Turin, Italy"},{"name":"Immunogenetics and Transplant Biology Service, Citt\u00e0 Della Salute e Della Scienza University Hospital, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renzhi","family":"Cai","sequence":"additional","affiliation":[{"name":"Endocrine, Polypeptide, and Cancer Institute, Veterans 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Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew V.","family":"Schally","sequence":"additional","affiliation":[{"name":"Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125, USA"},{"name":"South Florida VA Foundation for Research and Education, Miami, FL 33125, USA"},{"name":"Divisions of Hematology\/Oncology and Endocrinology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33101, USA"},{"name":"Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4164-7313","authenticated-orcid":false,"given":"Riccarda","family":"Granata","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, 10126 Turin, 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