SFEBES2016 Poster Presentations Neuroendocrinology and pituitary (34 abstracts)
Use of biguanides in the treatment of pituitary adenomas, an in vitro approach
Alejandro Ibáñez-Costa 1, , Ma Carmen Vázquez-Borrego 2 , Antonio C. Fuentes-Fayos 2 , Eva Venegas-Moreno 3 , Ma Ángeles Gálvez 4 , Alfonso Soto-Moreno 3 , Rhonda D. Kineman 5 , Justo P. Castaño 2 & Raúl M. Luque 2
1Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK; 2Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC); Department of Cell Biology, Physiology and Immunology, University of Córdoba; Hospital Universitario Reina Sofía (HURS); Campus de, Córdoba, Spain; 3Metabolism and Nutrition Unit, Hospital Virgen del Rocío; Instituto de Biomedicina de Sevilla Sevilla (IBIS), Sevilla, Spain; 4Service of Endocrinology and Nutrition, HURS/
IMIBIC, Córdoba, Spain; 5Research and Development Division, Jesse Brown Veterans Affairs Medical Center and Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois, USA.
Pituitary adenomas (PA) comprise a commonly underestimated pathology in terms of incidence and associated morbi-mortality. Although somatostatin analogs and dopamine antagonists constitute the main medical treatments for PAs, an appreciable subset of patients are resistant or poorly responsive to these drugs and hence is crucial the search for new therapies. Biguanides such as metformin (MF; commonly used to treat type-2 diabetes), phenformin (PF) and buformin (BF) have been shown to exert antitumour actions in in different tumour types (brain, prostate, breast and lung cancers) but their actions in PA cells have not been reported. The aim of this study was to determine the in vitro effect of these biguanides on key functional parameters (hormone expression/secretion, signaling pathways and cell viability) in: normal pituitaries of two primate models (Papio anubis and Macaca fascicularis) and a series of 15 functioning (GH- and ACTH-secreting) and non-functioning PAs (NFPAs). The treatment with biguanides in normal primate pituitary cultures decreased GH, ACTH and FSH secretion and GH and ACTH mRNA expression. MF and PF treatment did not alter cell viability in both species, while reduced the cell viability, in a dose-dependent manner, in GH- and ACTH-secreting PAs and NFPAs. In primates, the use of inhibitors of different signalling pathways revealed that the inhibitory effect of MF on pituitary hormone release involved the activation of mTOR, PI3K intracellular calcium signaling and/or MAPK pathways. In line with this, in PA primary cultures the effect of biguanides might involve a calcium-dependent mechanism, since treatment with these biguanides clearly altered the kinetics of cytosolic free calcium. Taken together, our results reveal a clear inhibitory effect of biguanides on pituitary adenoma cell viability in vitro, and given their demonstrated clinical safety suggest a potential therapeutic role of these compounds for the treatment of PA patients.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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