Therapeutic Use of Metformin in Thyroid Cancer

Abstract

Thyroid cancer is a rare type of malignancy. However, thyroid cancer constitutes more than 90 % of endocrine tumors. Metformin (N', N'-dimethybiguanide) is the most commonly prescribed drug in the world, and the annual number of prescriptions for this drug exceeds 120 million. Metformin is the first-line oral treatment for patients with type II diabetes. Metformin has recently been investigated for potential anti-cancer activity in patients with thyroid cancer by stimulating the Adenosine Mono-Phosphate-Activated Protein Kinase (AMPK) pathway in some types of tumors. In general, the anti-cancer mechanism of metformin acts directly by blocking mitochondrial oxidative phosphorylation through down-regulation of mitochondrial complex I and mitochondrial glycerophosphate dehydrogenase. This leads to a state of metabolic stress that in turn stimulates the AMPK pathway due to ATP reduction, and leads to inhibition of the mechanical (mammalian) target of the rapamycin (mTOR) pathway, which subsequently inhibits cancer cell proliferation and stimulates apoptosis and autophagy with cell cycle perturbation. Metformin also acts in an independent manner, in addition to its indirect actions that target insulin resistance. In this review, we reviewed 21 studies on the use of metformin in thyroid cancer, which showed that administration of metformin in diabetic patients is associated with a reduced incidence of thyroid cancer. On the other hand, the use of metformin enhances the response to anticancer drugs in thyroid cancer. Overall, we need further prospective studies to elucidate the synergistic mechanism of metformin when it is used to treat thyroid cancer as adjuvant therapy with anticancer drugs.