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.

Keywords: clinical trials; endocrine tumors; mechanism of action; metformin; preclinical evidence.

Figure 1.

Different types of endocrine tumors.

Figure 2.

Mechanism of action of metformin in endocrine tumors: metformin is a negatively charged molecule that enters the cell through organic cation transporters (OCTs). After entering the cells, it can inhibit tumorigenesis through the following pathways. First, metformin, through its direct action, can inhibit complex 1 or mGPDH, either alone or together, to inhibit oxidative phosphorylation (OXPHOS). This inhibition of OXPHOS lowers the energy production (ATP synthesis) within the cells, which creates cellular stress in cancer cells. The reduction in ATP production increases both the AMP:ATP and ADP:ATP ratios, which activates AMPK. Activation of AMPK, in turn, leads to activation of tuberous sclerosis complex ½ (TSC ½), which inhibits the mTOR pathway. Second, metformin can inhibit insulin or insulin-like growth factor-1 (IGF-1) mediated activation of the RAS-MEK-ERK and PI3K-AKT pathways, which results in the inhibition of the mTOR pathway. Third, metformin-mediated activation of AMPK can inhibit phosphorylation of insulin receptor substrate-1 (IRS-1). IRS-1 is downstream of the IGF-1 pathway and upstream of the PI3K-AKT pathway. Inhibition of IRS-1 activity hampers AKT phosphorylation, which causes activation of the TSC complex and inhibition of the mTOR pathway. Last, metformin has other targets including STAT3, GSK3, and ATF3 in endocrine cells, but the exact pathway by which metformin targets these genes/proteins are not known.