Pituitary adenomas (PA) comprise a commonly underestimated pathology in terms of incidence and associated morbimortality. To date, somatostatin and dopamine analogs represent the main medical treatment, but an appreciable subset of patients are resistant or poorly responsive to these drugs. Therefore, the search for new approaches to control tumor growth and/or hormone secretion is crucial. Biguanides such as metformin (MF; commonly used to treat type-2 diabetes), phenformin (PF) and buformin (BF) have been shown to exert antitumor actions in different tumor types. Likewise, statins (such as atorvastatin or simvastatin) treatment have been also related to antineoplastic effects in several tumor types. Accordingly, the aim of this study was to elucidate the direct effect of biguanides and statins, alone or in combination, on key functional parameters (i.e. cell viability, hormone secretion, etc.) in human PA cell-cultures [non-functioning pituitary adenomas (NFPAs; n=8), corticotropinomas (ACTHomas; n=7) and somatotropinomas (GHomas; n=4)] and/or rodent pituitary cell-lines (AtT-20 and GH3). The results showed that biguanides and statins clearly inhibited cell viability in pituitary cell-lines (being PF and simvastatin the most effective compounds, respectively), and a similar effect was also observed with biguanides in all PA-subtypes. Additionally, the co-administration of biguanides and statins did not alter the initial inhibitory actions of these compounds separately in cell lines, which might suggest that biguanides and statins exert their effects through common signaling pathways. In addition, biguanides were able to significantly reduce GH and ACTH secretion in GH3 and AtT-20 cell lines, respectively. Taken together, our results reveal a clear inhibitory effect of biguanides and statins on PA cell viability and, given their demonstrated clinical safety, suggest a potential therapeutic role of these compounds for the treatment of patients with PA.
Funding: Junta de Andalucia (CTS-1406, BIO-0139), MINECO (BFU2013-43282-R), CIBERobn and Merck Serono. CIBER is an initiative of Instituto de Salud Carlos III, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain.
20 - 23 May 2017
European Society of Endocrinology