Effects of prolonged exposure to low dose metformin in thyroid cancer cell lines

Abstract

Background: Thyroid cancer is generally associated with an excellent prognosis, but there is significant long-term morbidity with standard treatment. Some sub-types however have a poor prognosis. Metformin, an oral anti-diabetic drug is shown to have anti-cancer effects in several types of cancer (breast, lung and ovarian cancer). The proposed mechanisms include activation of the Adenosine Mono-phosphate-activated Protein Kinase (AMPK) pathway and inhibition of the mTOR pathway (which promotes growth and proliferation). By inhibiting hepatic gluconeogenesis and increasing glucose uptake by muscles, metformin decreases blood glucose and circulating Insulin levels.Aims: Explore the effect of metformin on the growth and proliferation of thyroid cancer cell lines.Methods: The effects of metformin on thyroid cancer cell lines (FTC-133, K1E7, RO82-W-1, 8305C and TT) and normal thyroid follicular cells (Nthy-ori 3-1) were investigated using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay for cell proliferation; clonogenic assays; FACS analysis for apoptosis and cell cycle, H2A.X phosphorylation (γH2AX) assay for DNA repair and scratch assay for cell migration.Results: Metformin inhibited cell proliferation and colony formation at 0.03 mM and above and inhibited cell migration at 0.3 mM. At concentrations of 0.1 mM and above metformin increased the percentage of apoptotic cells and induced cell cycle arrest in G0/G1 phase at minimum concentration of 0.3 mM. Unlike previous reports, no effect on DNA repair response was demonstrated.Conclusion: Metformin suppressed growth of all thyroid cancer cell lines, at concentrations considered to be within in the therapeutic range for diabetic patients on metformin (<0.3 mM).

Valproic acid sensitizes metformin-resistant human renal cell carcinoma cells by upregulating H3 acetylation and EMT reversal

“…Besides, we suspected the fact, that the concentrations of metformin used in experimental studies were much higher than therapeutic human plasma concentrations [ 46 ], should be responsible for limiting the extrapolation of these findings to clinical practice. But a previous study demonstrated that even at low physiological doses (0.3-1 mM) exposure to metformin dampened proliferation, colony formation and migration, and the anti-proliferative effects [ 47 ]. In fact, although the inhibitory effects in most of laboratory studies were observed at concentrations which are at least 10-fold higher than the peak plasma concentration attained with typical dosing in diabetics, there are emerging studies which show that even very low doses of metformin could have substantial anti-cancerous effects [ 48 ].…”

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

“…A study published in 2017 analyzed the growth inhibitory effects of metformin on a variety of thyroid cancer cell lines with different origins -FTC, PTC, ATC and MTC -and normal thyroid follicular cells. Irrespective of the origin of thyroid cancer cell lines, metformin suppressed cellular proliferation at concentrations that fall within the therapeutic range (Kheder et al 2017). In another study, the anti-cancer effects of metformin were tested in two MTC cell lines, TT and MZ-CRC-1.…”

Metformin and thyroid carcinoma incidence and prognosis: A systematic review and meta-analysis

“…Many preclinical studies [ 60 , 64 , 65 ] mentioned that metformin was related to cell growth inhibitory because of cell proliferation inhibition instead of induction of cell apoptosis or necrosis. This evidence indicated that patients who had monotherapy with metformin might not lead to complete remission of the carcinoma.…”