Inhibition of glucose metabolism with metformin decreases tumor proliferation in anaplastic thyroid cancer

Bixiao Zhao MD, PhD
Department of Surgery
Division of Surgical Oncology
Poster Overview

Anaplastic thyroid cancer (ATC) is a devastating malignancy without effect current treatments. In ATC and many other cancers, glucose is an essential nutrient required for cell growth and function. ATC cells are highly metabolically active and rapidly consume glucose, making these cells dependent on glucose in the cellular environment. Therefore, having elevated glucose levels in the bloodstream would be beneficial for tumor cells. Indeed, diabetes has been associated with increased risk of developing many types of malignancies, including thyroid cancer. Metformin is a commonly used antidiabetic drug that lowers blood glucose levels and improves insulin sensitivity. Given this, we hypothesized that glucose restriction and metformin administration would suppress ATC.

After cultivating ATC cells at different glucose concentrations with or without metformin, we discovered that tumor cells grew faster when the surrounding glucose levels were high.

Importantly, metformin significantly diminished ATC growth and cell migration. These inhibitory effects were strongest in the lowest glucose setting, then became progressively weaker as the glucose levels increased. This indicates that metformin is most effective when the surrounding glucose concentration is kept low. Overall, our findings suggest that using metformin while restricting glucose intake may be an effective strategy to treat ATC.

Scientific Abstract

Introduction: Anaplastic thyroid cancer (ATC) is a rare but devastating malignancy. Glucose is an essential nutrient for cancer. Metformin is a commonly used antidiabetic drug that lowers blood glucose levels and improves insulin sensitivity. We hypothesized that glucose restriction and metformin administration would inhibit ATC.

Methods: ATC cell lines 8505C and JL30 were grown in media containing high (25 mM) (HG), medium (11 mM) (MG), or low (3 mM) (LG) glucose concentrations with supplemental administration of metformin (5 mM). Cell proliferation and migration assays were performed.

Results: Glucose restriction diminished ATC proliferation in both 8505C and JL30 cell lines (P <0.05 and P < 0.001, respectively, LG versus HG). Addition of metformin decreased cell proliferation at nearly all glucose concentrations (P < 0.01 for all except HG in 8505C) and reduced cell migration in both cell lines (P < 0.01 for all comparisons except P < 0.05 for HG in 8505C). Elevation of glucose levels partially rescued metformin-mediated inhibition of growth and migration in a dose-dependent manner.

Conclusions: Glucose restriction and metformin administration inhibited ATC growth and function. Suppression of glucose metabolic pathways using metformin may represent an effective strategy in the treatment of ATC.

Clinical Implications
Our data show that metformin reduces the growth and migration of anaplastic thyroid cancer (ATC) cells, especially in a low glucose setting. Administration of metformin combined with glucose restriction may be a novel and effective strategy to treat ATC.
Research Areas
Authors
Bixiao Zhao, MD, PhD; Abha Aggarwal, PhD; Jessica Marshall, BSc; Matthew Nehs, MD
Principal Investigator
Matthew Nehs

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