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

Our plain-English summary of Antagonist of Growth Hormone-Releasing Hormone Potentiates the Antitumor Effect of Pemetrexed and Cisplatin in Pleural Mesothelioma, by I. Gesmundo, F. Pedrolli, N. Vitale, et al (International Journal of Molecular Sciences, 2022).

The study

• Authors: I. Gesmundo, F. Pedrolli, N. Vitale, A. Bertoldo, G. Orlando, D. Banfi, G. Granato, R. Kasarla, F. Balzola, S. Deaglio, R. Cai, W. Sha, M. Papotti, E. Ghigo, A.V. Schally, R. Granata
• Journal: International Journal of Molecular Sciences
• Published: 2022;23(19)
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This was a laboratory and animal study. It did not study people or asbestos exposure. The authors tested whether an experimental drug, the growth hormone-releasing hormone antagonist MIA-690, made the standard chemotherapy drugs cisplatin and pemetrexed work better against pleural mesothelioma. They used a human biphasic mesothelioma cell line, MSTO-211H. The cells were grown in dishes and also implanted in immune-deficient mice, with nine mice in each of four groups treated for 28 days. In cells, the three drugs together reduced cell survival and growth and increased cell death more than chemotherapy alone. In mice at day 28, tumor volume was 47% lower with the combination than with an inactive vehicle and 18% lower than with chemotherapy alone. Tumor weight was 58% and 22% lower, respectively. The combination also lowered several growth and inflammation markers, although a reduction in IGF-1 compared with chemotherapy alone was not statistically significant. The authors concluded that these antagonists could improve standard therapy in pleural mesothelioma.

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) cell experiments and an animal experiment in mice with implanted human mesothelioma tumors (xenografts)
• Who was studied: The human biphasic mesothelioma cell line MSTO-211H, and immune-deficient NOD/SCID/gamma chain knockout (NSG) male mice implanted with these cells. The mice were randomized into four groups of nine and treated for 28 days, in Turin, Italy.
• Exposure: No asbestos exposure was studied. The treatments were the GHRH antagonist MIA-690 (5 µg daily under the skin), cisplatin (5 mg/kg) and pemetrexed (100 mg/kg) given into the abdomen on set days, the three together, or an inactive vehicle. In cells, the doses were 1 µM MIA-690, 2 µM cisplatin and 50 nM pemetrexed.
• Main results:
  • In MSTO-211H cells, adding MIA-690 to cisplatin and pemetrexed further reduced cell viability and proliferation and increased apoptosis (cell death), compared with cisplatin and pemetrexed alone.
  • In cells, the combination index for the three drugs together was 0.33, which the authors described as a strong synergistic effect.
  • In mice, MIA-690 alone reduced tumor volume by 15% at day 21 and 20% at day 28 compared with vehicle.
  • In mice, cisplatin plus pemetrexed reduced tumor growth by 22% at day 21 and 26% at day 28.
  • In mice, the three-drug combination reduced tumor volume by 35% at day 21 and 47% at day 28 compared with vehicle, and by 15% and 18% compared with cisplatin plus pemetrexed alone.
  • At the end of the experiment, tumor weight in the combination group was 58% lower than with vehicle and 22% lower than with cisplatin plus pemetrexed.
  • In tumor tissue, the combination reduced markers of cell proliferation and increased markers of cell death more than chemotherapy alone.
  • The combination lowered genes involved in inflammation and tumor development (iNOS, COX-2, MMP2, MMP9, HMGB1) more than chemotherapy alone.
  • The reduction in IGF-1 with the combination, compared with chemotherapy alone, was slight and not statistically significant.
  • MIA-690 alone produced a slight, not statistically significant reduction in STAT3 activation.
• The authors' conclusion: The authors concluded that their results suggest GHRH antagonists could improve the anticancer effectiveness of standard therapy in pleural mesothelioma.

Topics

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

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Cisplatin, Pleural Mesothelioma, Prognosis, Lung Cancer, Mesothelioma, Apoptosis, High Mobility Group Box 1 (HMGB1).

Related studies

• Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of human malignant pleural mesothelioma — T. Villanova, I. Gesmundo, et al. (2019)
• 2-Deoxy-glucose Enhances the Effect of Cisplatin and Pemetrexed in Reducing Malignant Pleural Mesothelioma Cell Proliferation But Not Spheroid Growth — I. Gerogianni, E. Pitaraki, et al. (2019)
• Cell-growth and migration inhibition of human mesothelioma cells induced by 3-O-methylfunicone from Penicillium pinophilum and cisplatin — E. Buommino, A. De Filippis, et al. (2012)
• Serum HMGB1 as a Potential Biomarker for Patients with Asbestos-Related Diseases — S. Ying, Z. Jiang, et al. (2017)
• Pro-oxidant activity of sulforaphane and cisplatin potentiates apoptosis and simultaneously promotes autophagy in malignant mesothelioma cells — Y.J. Lee, S.H. Lee (2017)
• Interaction and cross-resistance of cisplatin and pemetrexed in malignant pleural mesothelioma cell lines — M. Kitazono-Saitoh, Y. Takiguchi, et al. (2012)

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