ECE2014 Symposia Metformin: old dog, new tricks (3 abstracts)
The relative risk associated with diabetes and obesity is significantly higher for different carcinomas including thyroid cancer. There is some evidence that insulin resistance and as a consequence hyperinsulinemia rather than hyperglycemia are responsible for the higher prevalence of cancer in diabetic and obese patients. In the thyroid insulin/IGF-depending signalling is part of the mitogenic pathways that regulate benign and malignant growth. In diabetics with hyperinsulinemia metformin decreases circulating insulin levels and thereby reduces its growth-promoting effect on differentiated thyroid and thyroid cancer cells. As a thyroid-specific effect metformin lowers TSH level which is involved in the regulation of thyroid growth and is critical for the prognosis and outcome of thyroid cancer.
Beside these systemic effects, on the cellular level metformin antagonizes the growth-stimulatory effect of insulin, exerts an antimitogenic effect by inhibition of cell cycle progression and induction of apoptosis. In addition, metformin inhibits clonal cell growth of thyroid cancers cells and reduces formation of thyroid cancer spheres which are enriched with cancer stem cells. On the molecular level metformin exerts its antimitogenic effect by targeting insulin/IGF and AMPK/mTOR signalling pathways.
Remarkably, the antiproliferative effect of metformin is not restricted to differentiated thyroid cells, thyroid cancer cells and derived cancer stem cells but also operative in a doxorubicin-resistant thyroid carcinoma cell line. Metformin potentiates the antimitogenic effect of chemotherapeutic agents such as doxorubicin and cisplatin on undifferentiated thyroid carcinoma cells which allows dose reduction of these toxic drugs and in turn diminishes their side-effects. These findings suggest the well-tolerated and safe drug metformin as an adjuvant to chemotherapy of undifferentiated thyroid carcinomas which do not respond to radio-iodine treatment in diabetics and obese patients with insulin resistance and hyperinsulinemia.