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

Mol Cancer Ther. 2014 Dec;13(12):2805-16. doi: 10.1158/1535-7163.MCT-13-1091. Epub 2014 Oct 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Neoplasms / metabolism
  • Neoplasms / mortality
  • Neoplasms / pathology
  • Neoplasms / radiotherapy
  • Oxidative Stress / drug effects
  • Pyrimidinones / administration & dosage
  • Pyrimidinones / pharmacology*
  • Radiation Tolerance / drug effects*
  • Symporters / antagonists & inhibitors*
  • Thiophenes / administration & dosage
  • Thiophenes / pharmacology*
  • Tumor Burden / drug effects
  • Tumor Burden / radiation effects
  • Xenograft Model Antitumor Assays

Substances

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