Abstract
Background: Anaplastic thyroid cancer is a rare but devastating malignancy. Anaplastic thyroid cancer cells exhibit the Warburg effect by preferentially undergoing glycolysis even in aerobic conditions, leading to high glucose use. Here we assess if targeted inhibition of glycolysis can diminish anaplastic thyroid cancer growth and improve outcomes. Methods: Human anaplastic thyroid cancer cell line 8505C was grown in medium containing high (25 mmol/L) or low (3 mmol/L) glucose concentration and hexokinase II inhibitor 3-bromopyruvate (200 μM). Cellular proliferation, migration, and invasion were measured. An orthotopic xenograft model of anaplastic thyroid cancer was generated in nude mice using 8505C cells. Animals were provided standard chow or a ketogenic diet and treated with 3-bromopyruvate (1.8 mg/kg). Overall survival time was monitored. Necropsies were performed to harvest tumors for analysis. Results: Growth of 8505C in low-glucose medium with 3-bromopyruvate decreased cell proliferation by 89%, migration by 44%, and invasion by 73% (P < .001 for all) compared with high glucose. Animals concomitantly receiving a ketogenic diet and 3-bromopyruvate exhibited smaller tumor volumes (P = .03), slower tumor growth rates (P = .01), and improved overall survival (P = .006) compared with standard-diet control subjects. Monotherapy with a ketogenic diet or 3-bromopyruvate alone did not reduce tumor size or increase survival over the standard-diet control group. Conclusion: Glycolytic inhibition with 3-bromopyruvate inhibits tumor growth and extends survival in a murine model of anaplastic thyroid cancer when combined with the ketogenic diet. Thus, targeted glycolytic inhibition of anaplastic thyroid cancer exhibits context-specific utility and may only be effective during ketosis induced by dietary restriction of glycolytic inputs.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 227-234 |
| Number of pages | 8 |
| Journal | Surgery (United States) |
| Volume | 171 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2022 |
Funding
The authors Zhao, Aggarwal, Marshall, Barletta, Kijewski, and Nehs have no conflicts of interest to report. Dr. Lorch’s research is supported by Takeda, Bayer, and BMS. He has received consulting honoraria from Bayer and Novartis. However, none of these are relevant to the present study. Support for this research was provided by The Thyroid Cancer Survivors’ Association award given at the American Association of Endocrine Surgeons 2019 as well as National Institutes of Health grant T32DK007754. T32 funding was used to support the salary of author Zhao.
ASJC Scopus subject areas
- Surgery
