Biguanides exert antitumoral actions in pituitary tumor cells through AMPK-dependent and -independent mechanisms.

CONTEXT: Pituitary neuroendocrine tumors (PitNETs) comprise a commonly underestimated pathology in terms of incidence and associated morbimortality. Currently, an appreciable subset of patients is resistant or poorly responsive to the main current medical treatments [i.e. somatostatin-analogues (SSAs)/dopamine-agonists]. Thus, development/optimization of novel/available medical therapies is necessary. Biguanides (metformin/buformin/phenformin) are antidiabetic drugs that exert antitumoral actions in several tumor types, but their pharmacological effects on PitNETs are poorly known.

OBJECTIVE: We aimed to explore the direct effects of biguanides on key functions (cell-viability/hormone-release/apoptosis/signaling-pathways) in primary cell-cultures from human PitNETs and cell-lines. Additionally, we evaluated the combination of metformin with SSAs on cell-viability and hormone secretion.

DESIGN: A total of 13 corticotropinomas, 13 somatotropinomas, 13 non-functioning PitNETs, 3 prolactinomas and two 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.

RESULTS: Biguanides reduced cell-viability in all PitNETs and cell-lines (being phenformin 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-SSAs therapy did not enhance SSAs monotherapy effectiveness. Effects of biguanides on PitNETs could involve the modulation of AMPK-dependent ([Ca2+]i, PI3K/Akt) and independent (MAPK) mechanisms.

CONCLUSION: Altogether, our data unveil clear antitumoral effects of biguanides on PitNET cells, opening new avenues to explore their potential as drugs to treat these pathologies.