ECE2020 Oral Communications Young Investigators (12 abstracts)
Growth hormone-releasing hormone (GHRH) antagonists increase the sensitivity to radiotherapy in lung cancer cells
Iacopo Gesmundo 1 , Alessandro Dematteis 1 , Alessandro Fanciulli 1 , Francesca Romana Giglioli 2 , Renzhi Cai 3,4 , Wei Sha 3,4 , Umberto Ricardi 5 , Ezio Ghigo 1 , Andrew V Schally 3,4 & Riccarda Granata 1
1University of Turin, Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, Turin, Italy; 2Medical Physics Unit, A.O.U. Città della Salute e della Scienza, Turin, Italy; 3University of Miami Miller School of Medicine, Division of Endocrinology, Department of Medicine, Miami, Florida, United States; 4University of Miami Miller School of Medicine, Division of Medical Oncology, Department of Medicine, Miami, Florida, United States; 5University of Turin, Department of Oncology, Radiation Oncology, Turin, Italy
Growth hormone-releasing hormone (GHRH), apart from stimulating GH secretion in the pituitary, exerts many extrapituitary functions, including stimulation of cell proliferation and survival. GHRH and its receptor splice variants (SVs) are expressed in different cancer cell types, where they modulate cell growth. It has been shown that GHRH antagonists exert anticancer activities in a variety of tumors, including malignant pleural mesothelioma and lung cancer, one of the leading causes of cancer death worldwide. Radiotherapy with ionizing radiation (IR) is currently the first-line treatment for advanced stage lung cancer; however, IR is not always resolutive and is often associated with serious side effects. To date, the role of GHRH antagonists in sensitization of lung cancer to IR remains unknown. Thus, we aimed to verify the antitumor effect of last generation GHRH antagonists, MIA-602 and MIA-690, in human A549 non-small cell lung cancer (NSCLC) cells, in combination with IR. We found that, as previously reported, 24 h treatment with MIA-602 and MIA-690 reduced cell survival and growth in A549 cells NSCLC cells. Interestingly, both antagonists potentiated the inhibitory effect of IR (at 2 and 5 Gy) on cell survival and proliferation, and increased IR-induced apoptosis. Furthermore, MIA-602 and MIA-690 enhanced the IR-induced increase in p53 tumor suppressor protein and the inhibition in Bcl-2 antiapoptotic protein. These effects were paralleled by elevation in expression of genes involved in tumor progression (c-Myc, cyclin B1 and cyclin D1/2), angiogenesis [vascular endothelial growth factor (VEGF)], and invasion [(metalloproteases (MMP)-2, MMP-9 and E-cadherin)]. Ongoing experiments will assess the role of GHRH antagonists in human primary lung cancer cells, along with the regulation of pathways involved in DNA repair (Ku70, Ku80 and DNA-dependent protein kinase). Overall, these results suggest that, in addition to the previously reported inhibitory effects in lung cancer, MIA-602 and MIA-690 may enhance the sensitivity to radiotherapy, thereby increasing the IR-induced antitumor response.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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