ECE2019 Poster Presentations Pituitary and Neuroendocrinology 1 (72 abstracts)
Antitumor effects of growth hormone-releasing hormone (GHRH) antagonists in ACTH and GH-secreting pituitary adenoma cell lines
Alessandro Fanciulli 1 , Iacopo Gesmundo 1 , Giacomo Gamba 1 , Justo P Castaño 2 , Raùl M Luque 2 , Clara V Alvarez 3 , Carlos Dieguez 3 , Maria Chiara Zatelli 4 , Ezio Ghigo 1 , Andrew V Schally 5 & Riccarda Granata 1
1Division of Endocrinology, Diabetes and Metabolism, Department of Medical Science, University of Turin, Torino, Italy; 2Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain; 3Centro de Investigaciones Medicas (CIMUS) e Instituto de Investigaciones Sanitarias and Department of Physiology, University of Santiago de Compostela, Santiago de Compostela, Spain; 4Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy; 5Division of Endocrinology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
Pituitary neuroendocrine tumors (PitNETs) are mostly benign lesions originating from the anterior pituitary and represent 10–15% of all the intracranial neoplasms. PitNETs can be classified in non-secretory, clinically non-functioning pituitary adenomas (NFPAs), and secretory, comprising prolactin (PRL), growth hormone (GH) and adrenocoticotropic hormone (ACTH) PitNETs. Surgical resection is the first line treatment for PitNETs, whereas chemotherapy and radiotherapy are preferred for resistant or metastatic tumors. GH-releasing hormone (GHRH), apart from promoting pituitary GH secretion, exerts many extrapituitary functions, including stimulation of cell proliferation and survival. GHRH, GHRH receptor (GHRH-R) and splice variant 1 (SV1) of GHRH-R, are expressed in different cancer cell types, where they promote cell growth and tumor progression. Conversely, it has been shown that GHRH antagonists inhibit the growth of different tumors in vitro and in vivo; moreover, previous reports showed that first generation GHRH antagonists reduce the secretion of GH in tumoral rat GH-secreting (GH3) cells. However, to date the role of GHRH antagonists in PitNETs remains largely unknown. Thus, the aim of this study was to evaluate the effects of the novel GHRH antagonists, MIA-602 and MIA-690, on survival, apoptosis and hormone secretion using tumoral murine ACTH-secreting cells (AtT-20/D16v-F2) and tumoral rat PRL- and GH-secreting cells transfected with human GHRH-R (GH3-hGHRHR). Our results show that MIA-602 and MIA-690 dose-dependently reduced cell survival and promoted apoptosis in tumoral ACTH-secreting cells; moreover, we observed an increase in expression of the proapoptotic protein BAX and the tumor suppressor protein P53, paralleled by a reduction of the antiapoptotic protein Bcl-2. MIA-602 and MIA-690 also reduced colony formation and expression of c-Myc oncoprotein, indicating inhibitory activity on migration and proliferation. Furthermore, the combination of MIA-602 or MIA-690 with Temozolomide (TMZ), the main chemotherapy agent for PitNETs, produced a synergistic effect on inhibition of cell survival in AtT-20 cells. Importantly, ACTH secretion was also attenuated when these cells were treated with the antagonists. Finally, our preliminary results showed that GHRH antagonists reduced cell survival and promoted apoptosis in GH3-hGHRHR. Overall, these results demonstrate GHRH antagonists reduce aggressiveness features in PitNETs, suggesting the putative utility of these drugs as novel therapeutic tool for the treatment of these pathologies.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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