RT Journal Article
T1 Biguanides Exert Antitumoral Actions in Pituitary Tumor Cells Through AMPK-Dependent and -Independent Mechanisms.
A1 Vazquez-Borrego, Mari C
A1 Fuentes-Fayos, Antonio C
A1 Herrera-Martinez, Aura D
A1 L-Lopez, Fernando
A1 Ibañez-Costa, Alejandro
A1 Moreno-Moreno, Paloma
A1 Alhambra-Exposito, Maria R
A1 Barrera-Martin, Ana
A1 Blanco-Acevedo, Cristobal
A1 Dios, Elena
A1 Venegas-Moreno, Eva
A1 Solivera, Juan
A1 Gahete, Manuel D
A1 Soto-Moreno, Alfonso
A1 Galvez-Moreno, Maria A
A1 Castaño, Justo P
A1 Luque, Raul M
K1 AMP-activated protein kinases
K1 Antineoplastic agents
K1 Apoptosis
K1 Biguanides
K1 Cell line, tumor
AB 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.
PB Oxford University Press
YR 2019
FD 2019-03-06
LK http://hdl.handle.net/10668/13691
UL http://hdl.handle.net/10668/13691
LA en
NO 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
NO This work has been funded by the following grants: Junta de Andalucía (CTS-1406 to R.M.L., BIO-0139 to J.P.C.), Ministerio de Ciencia, Innovación y Universidades (BFU2016-80360-R to J.P.C., FJCI-2016-30825 to A.I.C.), andInstitutodeSaludCarlos III,co-fundedbyEuropeanUnion (ERDF/ESF, “Investing in Your Future”: PI16/00264 to R.M.L., CP15/00156 to M.D.G., and CIBERobn). CIBER is an initiative of Instituto de Salud Carlos III.
DS RISalud
RD Apr 5, 2025