Glycolytic inhibition with 3-bromopyruvate suppresses tumor growth and improves survival in a murine model of anaplastic thyroid cancer.

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.

• Authors: Bixiao Zhao, Abha Aggarwal, Jessica A Marshall, Justine A Barletta, Marie F Kijewski, Jochen H Lorch, Matthew A Nehs
• Journal: Surgery (Surgery) Vol. 171 Issue 1 Pg. 227-234 (01 2022) ISSN: 1532-7361 [Electronic] United States
• PMID: 34334212 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Pyruvates
• bromopyruvate

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation
• Combined Modality Therapy (methods)
• Diet, Ketogenic
• Female
• Humans
• Mice
• Pyruvates (pharmacology, therapeutic use)
• Thyroid Carcinoma, Anaplastic (pathology, therapy)
• Thyroid Neoplasms (pathology, therapy)
• Tumor Burden (drug effects)
• Warburg Effect, Oncologic (drug effects)
• Xenograft Model Antitumor Assays