Inhibition of monocarboxylate transporter-1 (MCT1) by AZD3965 enhances radiosensitivity by reducing lactate transport.

Abstract

Inhibition of the monocarboxylate transporter MCT1 by AZD3965 results in an increase in glycolysis in human tumor cell lines and xenografts. This is indicated by changes in the levels of specific glycolytic metabolites and in changes in glycolytic enzyme kinetics. These drug-induced metabolic changes translate into an inhibition of tumor growth in vivo. Thus, we combined AZD3965 with fractionated radiation to treat small cell lung cancer (SCLC) xenografts and showed that the combination provided a significantly greater therapeutic effect than the use of either modality alone. These results strongly support the notion of combining MCT1 inhibition with radiotherapy in the treatment of SCLC and other solid tumors.

• Authors: Becky M Bola, Amy L Chadwick, Filippos Michopoulos, Kathryn G Blount, Brian A Telfer, Kaye J Williams, Paul D Smith, Susan E Critchlow, Ian J Stratford
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 13 Issue 12 Pg. 2805-16 (Dec 2014) ISSN: 1538-8514 [Electronic] United States
• PMID: 25281618 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• AZD3965
• Lactates
• Monocarboxylic Acid Transporters
• Pyrimidinones
• Symporters
• Thiophenes
• monocarboxylate transport protein 1

Topics

• Animals
• Biological Transport
• Cell Line, Tumor
• Cluster Analysis
• Disease Models, Animal
• Female
• Glycolysis (drug effects)
• Humans
• Lactates (metabolism)
• Metabolomics
• Monocarboxylic Acid Transporters (antagonists & inhibitors)
• Neoplasms (drug therapy, metabolism, mortality, pathology, radiotherapy)
• Oxidative Stress (drug effects)
• Pyrimidinones (administration & dosage, pharmacology)
• Radiation Tolerance (drug effects)
• Symporters (antagonists & inhibitors)
• Thiophenes (administration & dosage, pharmacology)
• Tumor Burden (drug effects, radiation effects)
• Xenograft Model Antitumor Assays