ECE2024 Poster Presentations Late-Breaking (77 abstracts)
Growth hormone-releasing hormone (GHRH) antagonists enhance radiosensitivity in non-small cell lung cancer cells
Iacopo Gesmundo 1 , Francesca Pedrolli 1 , Francesca Romana Giglioli 2 , Alessia Bertoldo 1 , Vanesa Gregorc 3 , Anna Sapino 1,3 , Luisella Righi 4 , Renzhi Cai 5,6 , Wei Sha 6 , Mauro Giulio Papotti 7 , Ezio Ghigo 1 , Andrew V. Schally 5,6,8 , Umberto Ricardi 9 & Riccarda Granata 1
1Department of Medical Sciences, University of Turin, Turin, Italy; 2Medical Physics Unit, A.O.U. Città della Salute e della Scienza, Turin, Italy; 3Candiolo Cancer Institute, Fondazione del Piemonte per l’Oncologia (FPO)-IRCCS, Candiolo, Italy; 4Department of Oncology, Pathology Unit, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Italy; 5Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; 6South Florida VA Foundation for Research and Education, Veterans Affairs Medical Center, Miami, FL, United States; 7Department of Oncology, Pathology Unit, University of Turin, Turin, Italy; 8Department of Medicine, Divisions of Medical Oncology and Endocrinology, and Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, United States; 9Department of Oncology, Radiation Oncology, University of Turin, Turin, Italy
Growth hormone-releasing hormone (GHRH), apart from stimulating GH secretion in the pituitary, exerts many peripheral functions, including stimulation of cell proliferation and survival. In fact, GHRH and GHRH receptors (GHRH-Rs) are expressed in different cancer cell types, where they promote proliferation and survival. Conversely, GHRH antagonists exert antineoplastic activities in several tumors, including lung cancer, one of the leading causes of death by cancer worldwide. Currently, radiotherapy is an important treatment in non-small cell lung cancer (NSCLC) patients, even if lack of tumor control, both locally and/or distantly, is quite common. Although different studies have demonstrated the ability of GHRH antagonists to potentiate the anticancer effect of chemotherapy, the role of these peptides in combination with radiotherapy remains unexplored. Thus, we explored the antitumor role of GHRH antagonists of MIA class, MIA-602 and MIA-690 in combination with radiotherapy, in human A549 and H522 NSCLC cells and primary lung adenocarcinoma cells. Our results revealed that MIA-602 and MIA-690, besides exerting inhibitory effects as single agents, potentiated the cytotoxic and antiproliferative effects of ionizing radiations (IR) in NSCLC and adenocarcinoma cells exposed to single doses of IR (2, 5 or 10 Gy). Furthermore, MIA-690 reduced the expression of GHRH-Rs and insulin-like growth factor (IGF)-I in A549 cells treated with 5 Gy IR. MIA-690 also potentiated the radiotherapy-induced inhibition of colony formation and expression of cell cycle promoters, while upregulating cell cycle inhibitors such as p21 and p27. The proapoptotic function of IR was enhanced by MIA-690, along with modulation of apoptosis effectors and elevation of p53 tumor suppressor protein. Mechanistically, MIA-690 also counteracted the response of A549 cells to IR by inhibiting proliferative, inflammatory, and oxidative pathways, such as PI3K/Akt, STAT3, NF-κB and COX2. Finally, MIA-690 hindered the IR-induced epithelial-mesenchymal transition (EMT) by upregulating mRNA for E-cadherin, while reducing vimentin, metalloproteinase (MMP)-2 and -9 and vascular endothelial growth factor (VEGF). Overall, these findings suggest potential application for GHRH antagonists in combination with radiotherapy for the treatment of NSCLC.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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