Effects of two mTOR inhibitors on in-vitro models of GH-secreting pituitary adenomas

Background: Gigantism and acromegaly are the main consequences of GH excess, mainly due to a pituitary adenoma. Surgery is the first therapeutic option, but also medical therapy is employed, being represented mostly by somatostatin analogues (SSA), that reduce both tumour mass and GH hypersecretion. However about 10% of patients is resistant to SSA. PI3K/Akt/mTOR pathway, activated by growth-factors such as IGF1, is important in regulating many cellular processes (viability, apoptosis and cell cycle), and it is deregulated in several neoplasms including GH-secreting pituitary tumours. Aim of the study: To understand how PI3K/Akt/mTOR pathway can influence viability and GH secretion in pituitary adenomas, we employed two inhibitors (Everolimus, mTOR inhibitor, and NVP-BEZ235, mTOR and PI3K inhibitor), evaluating their effects in presence or in absence of IGF1. Material and methods: We employed two GH-secreting pituitary adenoma rat cell lines and we assessed cell viability. Culture medium was collected to evaluate GH secretion by ELISA. Results: Both compounds (10–500 nM) caused a significant reduction in cell viability up to 60% in the two cell lines. On the other hand, IGF-1 induced cell viability by 60% as compared to control cells in GH3 cells and by 40% in GH4C1 cells. This effect was efficiently counteracted in both lines by Everolimus and NVP-BEZ235, indicating that these compounds could act, at least in part, on IGF-1 activated pathways. GH secretion was reduced by IGF1 in both cell lines; this effect was enhanced by Everolimus, but not by NVP-BEZ235 in both cell lines. Conclusions: Our results suggest that both compounds interfere with IGF1 signalling in GH-secreting rat cell lines, that could be used as a model to identify alternative pharmacological targets for GH-secreting pituitary adenomas resistant to SSA therapy.