Publication: Biguanides Exert Antitumoral Actions in Pituitary Tumor Cells Through AMPK-Dependent and -Independent Mechanisms.
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Identifiers
Date
2019-03-06
Authors
Vazquez-Borrego, Mari C
Fuentes-Fayos, Antonio C
Herrera-Martinez, Aura D
L-Lopez, Fernando
Ibañez-Costa, Alejandro
Moreno-Moreno, Paloma
Alhambra-Exposito, Maria R
Barrera-Martin, Ana
Blanco-Acevedo, Cristobal
Dios, Elena
Advisors
Journal Title
Journal ISSN
Volume Title
Publisher
Oxford University Press
Abstract
Pituitary neuroendocrine tumors (PitNETs) are a commonly underestimated pathology in terms of incidence and associated morbimortality. Currently, an appreciable subset of patients are resistant or poorly responsive to the main current medical treatments [i.e., synthetic somatostatin analogs (SSAs) and dopamine agonists]. Thus, development and optimization of novel and available medical therapies is necessary. Biguanides (metformin, buformin, and phenformin) are antidiabetic drugs that exert antitumoral actions in several tumor types, but their pharmacological effects on PitNETs are poorly known. We aimed to explore the direct effects of biguanides on key functions (cell viability, hormone release, apoptosis, and signaling pathways) in primary cell cultures from human PitNETs and cell lines. Additionally, we evaluated the effect of combined metformin with SSAs on cell viability and hormone secretion. A total of 13 corticotropinomas, 13 somatotropinomas, 13 nonfunctioning PitNETs, 3 prolactinomas, and 2 tumoral pituitary cell lines (AtT-20 and GH3) were used to evaluate the direct effects of biguanides on cell viability, hormone release, apoptosis, and signaling pathways. Biguanides reduced cell viability in all PitNETs and cell lines (with phenformin being the most effective biguanide) and increased apoptosis in somatotropinomas. Moreover, buformin and phenformin, but not metformin, reduced hormone secretion in a cell type-specific manner. Combination metformin/SSA therapy did not increase SSA monotherapy effectiveness. Effects of biguanides on PitNETs could involve the modulation of AMP-activated protein kinase-dependent ([Ca2+]i, PI3K/Akt) and independent (MAPK) mechanisms. Altogether, our data unveil clear antitumoral effects of biguanides on PitNET cells, opening avenues to explore their potential as drugs to treat these pathologies.
Description
MeSH Terms
Cell survival
Humans
Hypoglycemic agents
Neuroendocrine tumors
Pituitary neoplasms
Signal transduction
Humans
Hypoglycemic agents
Neuroendocrine tumors
Pituitary neoplasms
Signal transduction
DeCS Terms
Hipoglucemiantes
Neoplasias hipofisarias
Supervivencia celular
Transducción de señal
Tumores neuroendocrinos
Neoplasias hipofisarias
Supervivencia celular
Transducción de señal
Tumores neuroendocrinos
CIE Terms
Keywords
AMP-activated protein kinases, Antineoplastic agents, Apoptosis, Biguanides, Cell line, tumor
Citation
Vázquez-Borrego MC, Fuentes-Fayos AC, Herrera-Martínez AD, L-López F, Ibáñez-Costa A, Moreno-Moreno P, et al. Biguanides Exert Antitumoral Actions in Pituitary Tumor Cells Through AMPK-Dependent and -Independent Mechanisms. J Clin Endocrinol Metab. 2019 Aug 1;104(8):3501-3513