Background: Pituitary adenomas represent a commonly underestimated pathology in terms of incidence and associated morbimortality. Additionally, some patients poorly respond or develop resistance to current medical treatments [i.e. somatostatin analogues (SSAs) and dopamine agonists]. In this context, it is necessary to develop novel and/or optimize currently available medical therapies. Biguanides (metformin, buformin and phenformin) are antidiabetic drugs that have been described to exert anti-proliferative effects in several tumor types. However, their pharmacological effects on different pituitary tumor cells are poorly known.
Aims: We aimed to explore the direct effects of biguanides on key functional parameters(cell viability, hormone release, apoptosis, and signaling pathways) in primary cell cultures from human functioning (GH-, PRL- and ACTH-secreting cells) and non-functioning pituitary tumors (NFPTs). Additionally, we evaluated the effect of the combination therapy of metformin with SSAs on cell viability and hormone secretion.
Patients and methods: The role of the pre-surgery treatment with metformin was evaluated in 62 NFPTs, 42 ACTH-secreting and 28 GH-secreting pituitary tumors that underwent surgery. Additionally, primary cell cultures from 13 corticotropinomas, 13 somatotropinomas, 13 NFPTsand 3 prolactinomas were used. Cell viability, hormone release, apoptosis and signaling pathways were evaluated using validated methods.
Results: Pre-surgery treatment with metformin was not associated with tumor size, extrasellar growth, hormone secretion or clinical evolution. In human primary cell cultures, biguanides reduced cell viability in all types of pituitary tumorsand increased apoptosis in GH-secreting tumors. Phenformin was the most effective antiproliferative drug. Buformin and phenformin, but not metformin, reduced hormone secretion in a cell type specific manner. Finally, the combination therapy of metformin with SSAs did not increase the effectiveness of SSAs as monotherapy in corticotropinomas or somatotropinomas, butcombination therapy of metforminwith octreotide and pasireotide in NFPTs seemed to produce a higher decrease on cell viability as compared to the different treatments alone. These effects of biguanides on pituitary tumors may be explained by the modulation of AMPK-dependent (intracellular calcium, PI3K/Akt pathways) and/or -independent (ERK pathway) mechanisms.
Conclusion: In conclusion, our study provides primary evidence that biguanides exert important anti-proliferative and anti-secretory effects in different pituitary tumor cell types and pave the way to consider these compounds as a potential new therapeutic optio n in the treatment of these severe pathologies.
18 - 21 May 2019
European Society of Endocrinology