Biguanides Exert Antitumoral Actions in Pituitary Tumor Cells Through AMPK-Dependent and -Independent Mechanisms

Abstract

Context 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. Objective 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. Design 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. Results 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. Conclusion Altogether, our data unveil clear antitumoral effects of biguanides on PitNET cells, opening avenues to explore their potential as drugs to treat these pathologies.

Splicing Machinery is Dysregulated in Pituitary Neuroendocrine Tumors and is Associated with Aggressiveness Features

“…Thus, our results demonstrate for the first time that treatment with pladienolide-B inhibits cell viability/proliferation in all PitNETs subtypes tested and in AtT-20 and GH3 cell lines, which compares well with the reduction on cell viability and colony formation observed in HeLa cells [33] and with recent data from our group demonstrating that pladienolide-B reduced proliferation, migration and tumorspheres-formation in prostate cancer cells [33]. Interestingly, NFPTs were less sensitive to the effect of pladienolide-B compared to GHomas or ACTHomas, which is in line with previous observations in response to other pharmacological treatments in NFPTs [42,43,74]. Notably, pladienolide-B was also able to reduce GH secretion after 24 h of incubation, a relevant result since tumor hypersecretion is linked to most of the symptoms caused by GHomas.…”

The role of an anti-diabetic drug metformin in the treatment of endocrine tumors

“…In ACTH-secreting AtT20 cells, metformin inhibited cell proliferation by activating the AMPK signaling pathway and inhibiting the IGF-1R/AKT/mTOR pathway. In a recently published study performed on primary cell cultures derived from PitNETs, metformin treatment inhibited cell viability in ACTH-secreting adenomas and non-functioning PAs but not in GH-secreting adenomas and prolactinomas (Vázquez-Borrego et al 2019).…”

How treatments with endocrine and metabolic drugs influence pituitary cell function

“…Moreover, metformin did not affect ACTH, GH and prolactin secretion, although a higher concentration was used (10 mM) compared with the previous cited study. Combined treatments with metformin and a somatostatin analogue were not more effective than somatostatin analogue monotherapy (92). In the same study, phenformin, which is not used clinically due to higher risk of lactic acidosis, was more effective than metformin and reduced cell viability in all pituitary adenomas.…”

“…Finally, metformin indirectly targets different intracellular signalling pathways regulating protein synthesis, cell growth and differentiation, cell cycle progression and cell death. AMPK activation plays a central role in the effects of metformin on cell signalling but also AMPK-independent effects have been shown (12,13,16,91,92). In the last decade, preclinical studies have accumulated that report on the possible role of metformin as an adjuvant agent in the medical treatment of pituitary adenomas (16).…”