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

Abstract

Incidence of endocrine cancers is rising every year. Over the last decade, evidence has accumulated that demonstrates the anti-cancer effects of an anti-diabetic drug, metformin, in endocrine malignancies. We performed a literature review utilizing the PubMed, Medline and clinicaltrials.gov databases using the keyword ‘metformin’ plus the following terms: ‘thyroid cancer’, ‘thyroid nodules’, ‘parathyroid’, ‘hyperparathyroidism’, ‘adrenal adenoma’, ‘Cushing syndrome’, ‘hyperaldosteronism’, ‘adrenocortical cancer’, ‘neuroendocrine tumor (NET)’, ‘pancreatic NET (pNET)’, ‘carcinoid’, ‘pituitary adenoma’, ‘pituitary neuroendocrine tumor (PitNET)’, ‘prolactinoma’, ‘pheochromocytoma/paraganglioma’. We found 37 studies describing the preclinical and clinical role of metformin in endocrine tumors. The available epidemiological data show an association between exposure of metformin and lower incidence of thyroid cancer and pNETs in diabetic patients. Metformin treatment has been associated with better response to cancer therapy in thyroid cancer and pNETs. Preclinical evidence suggests that the primary direct mechanisms of metformin action include inhibition of mitochondrial oxidative phosphorylation via inhibition of both mitochondrial complex I and mitochondrial glycerophosphate dehydrogenase, leading to metabolic stress. Decreased ATP production leads to an activation of a cellular energy sensor, AMPK, and subsequent downregulation of mTOR signaling pathway, which is associated with decreased cellular proliferation. We also describe several AMPK-independent mechanisms of metformin action, as well as the indirect mechanisms targeting insulin resistance. Overall, repositioning of metformin has emerged as a promising strategy for adjuvant therapy of endocrine tumors. The mechanisms of synergy between metformin and other anti-cancer agents need to be elucidated further to guide well-designed prospective trials on combination therapies in endocrine malignancies.

How treatments with endocrine and metabolic drugs influence pituitary cell function

“…Based on a more recent work addressing the direct effects of biguanides on the expression and secretion of all the anterior pituitary hormones in non-human primate pituitary cells in vitro, metformin significantly reduced GH expression and secretion and was active at micromolar concentrations (46), not so far from the circulating concentrations of metformin related to its therapeutic glucose-lowering effect in humans (16). Since metformin is an indirect AMPK activator, these data may further support the conclusions derived from the previously mentioned data in rat pituitary cells.…”

“…For years, AMPK has been considered a possible therapeutic target in different kinds of neoplasia, since it is involved in the regulation of cell metabolism and cell survival in normal and in tumor cells and is known to negatively regulate intracellular signalling downstream of growth factor receptors (12,15,17,21,22,25). The potential of metformin as an anticancer agent has been documented in diabetic patients, since the treatment with metformin has been related to a lower cancer incidence compared to alternative anti-diabetic drugs (16,84,85). Metformin is a biguanide and a well-known, first-choice drug for type 2 diabetic patients.…”

“…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).…”

“…This activity is mediated by both AMPK-dependent and AMPK-independent mechanisms. As to the translational relevance of the preclinical studies, there are some limitations (16).…”

“…Finally, AMPK regulates cell viability and cell growth and is regarded as a drug discovery target for tumor therapy (14,15). Metformin is currently being investigated for anti-tumor effects in endocrine malignancies (16). The last section of this review explores the results of preclinical studies aimed at investigating the effects of AMPK activation and the effects of metformin on pituitary tumor cells published in the last decade.…”