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Article

Growth Hormone-Releasing Hormone Antagonists Increase Radiosensitivity in Non-Small Cell Lung Cancer Cells

by
Iacopo Gesmundo
1,2,
Francesca Pedrolli
1,2,
Francesca Romana Giglioli
3,
Florian Jazaj
1,2,
Giuseppina Granato
1,2,
Alessia Bertoldo
1,2,
Federica Bistolfi
1,2,
Vanesa Gregorc
4,
Anna Sapino
2,4,
Luisella Righi
5,
Renzhi Cai
6,7,
Wei Sha
7,
Medhi Wangpaichitr
6,7,8,9,
Mauro Papotti
10,
Ezio Ghigo
1,2,
Umberto Ricardi
11,
Andrew V. Schally
6,7,8,9 and
Riccarda Granata
1,2,*
1
Division of Endocrinology, Diabetes and Metabolism, 10126 Turin, Italy
2
Department of Medical Sciences, University of Turin, 10126 Turin, Italy
3
Medical Physics Unit, A.O.U. Città della Salute e Della Scienza, 10126 Turin, Italy
4
Candiolo Cancer Institute, Fondazione del Piemonte per l’Oncologia (FPO)-IRCCS, 10060 Candiolo, Italy
5
Department of Oncology, Pathology Unit, University of Turin, San Luigi Gonzaga Hospital, 10043 Orbassano, Italy
6
Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125, USA
7
South Florida VA Foundation for Research and Education, Veterans Affairs Medical Center, Miami, FL 33125, USA
8
Department of Medicine, Divisions of Medical/Oncology and Endocrinology, and the Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
9
Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
10
Department of Oncology, Pathology Unit, University of Turin, and Città Della Salute e Della Scienza Hospital, 10126 Turin, Italy
11
Department of Oncology, University of Turin, 10126 Turin, Italy
 
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Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(7), 3267; https://doi.org/10.3390/ijms26073267
Submission received: 19 November 2024 / Revised: 26 March 2025 / Accepted: 28 March 2025 / Published: 1 April 2025
(This article belongs to the Special Issue The Role of Hormonal Receptors in Cancer: Molecular Mechanisms and Targeted Therapies)
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Abstract

Growth hormone-releasing hormone (GHRH) antagonists exert antitumor functions in different experimental cancers. However, their role in combination with radiotherapy in non-small cell lung cancer (NSCLC) remains unknown. Therefore, we investigated the radiosensitizing effect of GHRH antagonists in NSCLC. A549 and H522 NSCLC cell lines were exposed to ionizing radiation (IR) and GHRH antagonists MIA-602 and MIA-690, either individually or in combination. Cell viability and proliferation were evaluated by MTT, BrdU, flow cytofluorimetry, and clonogenic assays; gene and protein expression, signaling pathways, and apoptosis were analyzed by real-time PCR, Western blot, annexin staining, and caspase-3 assay. GHRH antagonists showed antitumor effects alone and potentiated IR-induced inhibition of cell viability and proliferation. The combination of MIA-690 and IR decreased the expression of GHRH receptor, its oncogenic splice variant 1, and IGF1 mRNA levels. Additionally, cell cycle inhibitors and proapoptotic markers were upregulated, whereas cyclins, oncogenic MYC, and the antiapoptotic protein Bcl-2 were downregulated. Radioresistance was prevented by MIA-690, which also blunted epithelial–mesenchymal transition by enhancing E-cadherin and reducing mesenchymal, oxidative, and proangiogenic effectors. Finally, both MIA-602 and MIA-690 enhanced radiosensitivity in primary human NSCLC cells. These findings highlight the potential of GHRH antagonists as radiosensitizers in NSCLC treatment.
Keywords: GHRH; GHRH antagonists; NSCLC; ionizing radiation; radiosensitivity GHRH; GHRH antagonists; NSCLC; ionizing radiation; radiosensitivity
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MDPI and ACS Style

Gesmundo, I.; Pedrolli, F.; Giglioli, F.R.; Jazaj, F.; Granato, G.; Bertoldo, A.; Bistolfi, F.; Gregorc, V.; Sapino, A.; Righi, L.; et al. Growth Hormone-Releasing Hormone Antagonists Increase Radiosensitivity in Non-Small Cell Lung Cancer Cells. Int. J. Mol. Sci. 2025, 26, 3267. https://doi.org/10.3390/ijms26073267

AMA Style

Gesmundo I, Pedrolli F, Giglioli FR, Jazaj F, Granato G, Bertoldo A, Bistolfi F, Gregorc V, Sapino A, Righi L, et al. Growth Hormone-Releasing Hormone Antagonists Increase Radiosensitivity in Non-Small Cell Lung Cancer Cells. International Journal of Molecular Sciences. 2025; 26(7):3267. https://doi.org/10.3390/ijms26073267

Chicago/Turabian Style

Gesmundo, Iacopo, Francesca Pedrolli, Francesca Romana Giglioli, Florian Jazaj, Giuseppina Granato, Alessia Bertoldo, Federica Bistolfi, Vanesa Gregorc, Anna Sapino, Luisella Righi, and et al. 2025. "Growth Hormone-Releasing Hormone Antagonists Increase Radiosensitivity in Non-Small Cell Lung Cancer Cells" International Journal of Molecular Sciences 26, no. 7: 3267. https://doi.org/10.3390/ijms26073267

APA Style

Gesmundo, I., Pedrolli, F., Giglioli, F. R., Jazaj, F., Granato, G., Bertoldo, A., Bistolfi, F., Gregorc, V., Sapino, A., Righi, L., Cai, R., Sha, W., Wangpaichitr, M., Papotti, M., Ghigo, E., Ricardi, U., Schally, A. V., & Granata, R. (2025). Growth Hormone-Releasing Hormone Antagonists Increase Radiosensitivity in Non-Small Cell Lung Cancer Cells. International Journal of Molecular Sciences, 26(7), 3267. https://doi.org/10.3390/ijms26073267

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