System Maintenance Notice

Please note that maintenance work is scheduled between 4 AM and 5 AM - CET. During this time, you may experience reduced performance. Thanks for your patience.

Publications

Journal Article Epublish

PubMed: 40244089 DOI: 10.3390/ijms26073267

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

Int J Mol Sci 26(7)

Authors: Iacopo Gesmundo, Francesca Pedrolli, Francesca Romana Giglioli, Florian Jazaj, Giuseppina Granato, Alessia Bertoldo, Federica Bistolfi, Vanesa Gregorc, Anna Sapino, Luisella Righi, Renzhi Cai, Wei Sha, Medhi Wangpaichitr, Mauro Papotti, Ezio Ghigo, Umberto Ricardi, Andrew V Schally, Riccarda Granata

Affiliations

  • Division of Endocrinology, Diabetes and Metabolism, 10126 Turin, Italy.
  • Department of Medical Sciences, University of Turin, 10126 Turin, Italy.
  • Medical Physics Unit, A.O.U. Città della Salute e Della Scienza, 10126 Turin, Italy.
  • Division of Endocrinology, Diabetes and Metabolism, 10126 Turin, Italy. Department of Medical Sciences, University of Turin, 10126 Turin, Italy.
  • Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO)-IRCCS, 10060 Candiolo, Italy.
  • Department of Oncology, Pathology Unit, University of Turin, San Luigi Gonzaga Hospital, 10043 Orbassano, Italy.
  • Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125, USA. South Florida VA Foundation for Research and Education, Veterans Affairs Medical Center, Miami, FL 33125, USA.
  • South Florida VA Foundation for Research and Education, Veterans Affairs Medical Center, Miami, FL 33125, USA.
  • Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125, USA.
  • 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.
  • Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
  • Department of Oncology, Pathology Unit, University of Turin, and Città Della Salute e Della Scienza Hospital, 10126 Turin, Italy.
  • Department of Oncology, University of Turin, 10126 Turin, Italy.
  • Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33125, USA. South Florida VA Foundation for Research and Education, Veterans Affairs Medical Center, Miami, FL 33125, USA. 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. Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.

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 , 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.

MeSH

Cells, Radiation Tolerance, Lung, Growth Hormone-Releasing Hormone, Growth, Neoplasms, Carcinoma, Non-Small-Cell Lung, Hormones, Lung Neoplasms, Small Cell Lung Carcinoma, Hormone Antagonists, Growth Hormone