ECE2019 Guided Posters Obesity (1) (11 abstracts)
A new generation somatostatin-dopamine chimeric analogue exerts potent antitumoral actions on primary pituitary neuroendocrine tumor cells
Emilia Alors-Pérez 1, , Mari C Vazquez-Borrego 1, , Fernando L-Lopez 1, , Maria A Galvez-Moreno 1, , Antonio C Fuentes-Fayos 1, , Eva Venegas-Moreno 6 , Aura D Herrera-Martínez 1, , Cristobal Blanco-Acevedo 1, , Juan Solivera 1, , Tanya Landsman 8 , Manuel D Gahete 1, , Alfonso Soto-Moreno 6 , Michael D Culler 8 , Justo P Castaño 1, & Raul M Luque 1,
1Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain; 2Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain; 3Reina Sofia University Hospital (HURS), Cordoba, Spain; 4CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Cordoba, Spain; 5Service of Endocrinology and Nutrition, Reina Sofia University Hospital, Cordoba, Spain; 6Metabolism and Nutrition Unit, Virgen del Rocio University Hospital, Institute of Biomedicine of Seville (IBiS), Sevilla, Spain; 7Service of Neurosurgery, Reina Sofia University Hospital, Cordoba, Spain; 8IPSEN Bioscience, Cambridge, MA, USA.
Pituitary neuroendocrine tumors (PitNETs) constitute approximately 15% of all intracranial tumors and comprise a varied type of neoplasms that, despite being rarely metastatic, can cause severe comorbidities and increased mortality related to the mass effects and hormonal hypersecretion. The high expression levels of somatostatin and dopamine receptors in these tumors has led to the use of somatostatin analogues (SSAs) and dopamine agonists (DAs) as pharmacological treatments. Nevertheless, a high proportion of patients are or become resistant to these drugs, in that they are unable to respond clinically or biochemically to these treatments. In this context, somatostatin-dopamine chimeric compounds (dopastatins) were developed to increase the efficacy and improve the control of the disease compared with SSAs and/or DAs. The main objective of this study was to determine the direct therapeutic effects of a new generation dopastatin chimeric compound, BIM-065, on primary cell cultures from different PitNETs subtypes. To that end, a total of 31 PitNETs [9 corticotropinomas, 9 somatotropinomas, 2 prolactinomas and 11 non-functioning pituitary tumors (NFPTs)] were collected and dispersed cells were treated with BIM-065 to evaluate different functional endpoints such as cell viability, apoptosis, hormone release, expression levels of key genes and free cytosolic [Ca2+]i dynamics. Additionally, AtT-20 cell-line was used to evaluate signaling pathways in response to this chimeric compound. Our results demonstrate that BIM-065 decreased cell viability in all corticotropinomas and somatotropinomas, as well as, in AtT-20 cells. In contrast, in NFPTs (a tumor type commonly resistant to SSAs and DAs treatment), BIM-065 did not alter cell viability. Remarkably, we observed an increase on apoptosis, and a reduction on ACTH, GH and chromogranin-A secretion in corticotropinomas, somatotropinomas and NFPTs in response to the chimeric compound, respectively. These results were possibly mediated through the modulation of pivotal signaling cascades like [Ca2+]i kinetics and Akt- or ERK1/2-phosphorylation. Taken together, our results reveal a clear antitumoral effect of this new chimeric compound on different PitNETs subtypes, which suggests that this compound could be an efficacious therapeutic option to consider in the treatment of this pathology.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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