ECE2021 Oral Communications Oral Communications 3: Pituitary and Neuroendocrinology (6 abstracts)
Antitumor effects of growth hormone-releasing hormone (GHRH) antagonists in ACTH–and GH-secreting pituitary neuroendocrine tumor (PitNETs) cell lines
Iacopo Gesmundo 1 , Alessandro Fanciulli 1 , Clara V. Alvarez 2 , Carlos Dieguez 2 , Maria Chiara Zatelli 3 , Silvia Grottoli 1 , Emanuela Arvat 1 , Justo P. Castaño 4 , Renzhi Cai 5 , Wei Sha 5 , Antonio C. Fuentes-Fayos 4 , Raùl M. Luque 4 , Ezio Ghigo 1 , Andrew V. Schally 5 , 6 & Riccarda Granata 1
1University of Turin, Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, Turin, Italy; 2University of Santiago de Compostela and Complexo Hospitalario Universitario of Santiago de Compostela, Centro de Investigaciones Medicas (CIMUS) e Instituto de Investigaciones Sanitarias and Department of Physiology, Santiago de Compostela, Spain; 3University of Ferrara, Section of Endocrinology and Internal Medicine, Department of Medical Sciences, Ferrara, Italy; 4Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Reina Sofia University Hospital and University of Cordoba, Cordoba, Spain; 5University of Miami Miller School of Medicine, Division of Endocrinology, Department of Medicine, Miami, Florida, United States; 6University of Miami Miller School of Medicine, Division of Medical Oncology, Department of Medicine, Miami, Florida, United States
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). Surgical resection is the first line treatment for PitNETs, whereas chemotherapy and radiotherapy are preferred for resistant or metastatic tumors. Growth hormone-releasing hormone (GHRH), besides promoting pituitary GH secretion, exerts many extrapituitary functions, including stimulation of cell proliferation and survival. GHRH, GHRH receptor (GHRH-R) and its splice variant 1 (SV1), are expressed in different cancer cell types, where they promote cell proliferation and tumor progression. Conversely, GHRH antagonists inhibit the growth of different tumors in vitro and in vivo; moreover, it has been demonstrated that first generation GHRH antagonists reduce GH secretion in tumoral rat GH-secreting (GH3) cells. However, to date the role of GHRH antagonists in PitNETs remains largely unknown. Thus, we aimed to clarify the potential antitumor effects of last generation GHRH antagonists, MIA-602 and MIA-690 in ACTH-secreting PitNET cells (AtT-20/D16v-F2), rat PRL–and GH-secreting PitNET cells, transfected with human GHRH-R (GH3-hGHRHR), and in primary cells isolated from patients with PitNETs. Our results show that MIA-602 and MIA-690 dose-dependently reduced cell survival and promoted apoptosis in AtT-20 and GH3-hGHRHR; in addition, 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 the main chemotherapy drug temozolomide showed a synergistic effect on inhibition of AtT-20/D16v-F2 cell survival. In addition, both GHRH antagonists reduced the secretion of GH, but not PRL, in GH3-hGHRHR, but showed no activity on ACTH secretion in AtT20/D16v-F2. Finally, preliminary results show a potential antitumor role for MIA-602 and MIA-690, alone or in combination with the somatostatin analog octreotide, in human primary cells isolated from NFPAs and ACTH–or GH-secreting PitNETs. Overall, these results indicate that GHRH antagonists display antitumor activities in ACTH and GH tumor cells and suggest their potential use for the treatment of PitNETs, alone or in combination with standard therapies.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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