Combination Metabolic Inhibition of Glycolysis and Glutaminolysis Reduces Cellular Proliferation, Migration and Invasion in Anaplastic Thyroid Cancer
A. Aggarwal, Bixiao Zhao, Matthew Nehs
Brigham and Women's Hospital, Boston, MA, USA
Background: Anaplastic thyroid cancer (ATC) is a fatal malignancy, and current therapies remain ineffective. Glucose and glutamine are two nutrients required by cancer cells to increase their proliferation, growth, and metastases. We hypothesized that using 3-Bromopyruvate/3-BP (glycolytic inhibitor) and 6-Diazo-5-oxo-L-norleucine/DON (glutamine inhibitor) in a low-glucose environment would inhibit tumor cell proliferation and growth.
Methods: We cultured ATC cell-lines (JL30 and 8505C) in high (25mM) (HG), medium (16mM) (RG) or low (3mM) (LG) glucose concentrations for 96 hours, with or without supplemental administration of 3-BP (200uM) plus DON (250uM). We performed cell proliferation, migration and invasion assays.
Results: In 8505C, LG versus HG significantly lowered proliferation (1.4 vs. 2.0 OD, p<0.01), invasion (96 vs. 143 Relative Fluorescent Units/RFUs, p<0.001) and migration (531 vs. 876 RFUs, p<0.0001). Adding 3BP+DON to LG further inhibited proliferation (0.1 vs 1.4 OD, p<0.001), invasion (. 40 vs 96 RFUs, p<0.001) and migration (135 vs. 531 RFUs, p<.001). In JL30, LG versus HG significantly reduced migration (474 vs. 954 RFUs, p<0.0001); adding DON+3BP to LG augmented the reduction in migration (123vs. 474, p<0.0001). A significant reduction in proliferation (0.1 vs. 1.7 OD, p<0.001) and invasion (35 vs. 200 RFUs , p<0.001) were noted with the addition of 3BP+DON to LG compared to HG.
Conclusion: Addition of 3BP plus DON to a low-glucose environment significantly reduced cellular proliferation, migration and invasion in both ATC cell-lines. Simultaneous inhibition of glycolysis and glutaminolysis may be an effective adjuvant treatment for anaplastic thyroid carcinoma.
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