Aldo-keto reductases-mediated cytotoxicity of 2-deoxyglucose: A novel anticancer mechanism

Shiqing ZHANG, Kin Lam YUNG, Sookja Kim Chung, Sum Man Stephen Chung*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

2-Deoxyglucose (2DG) is a non-metabolizable glucose analog currently in clinical trials to determine its efficacy in enhancing the therapeutic effects of radiotherapy and chemotherapy of several types of cancers. It is thought to preferentially kill cancer cells by inhibiting glycolysis because cancer cells are more dependent on glycolysis for their energy needs than normal cells. However, we found that the toxicity of 2DG in cancer cells is mediated by the enzymatic activities of AKR1B1 and/or AKR1B10 (AKR1Bs), which are often overexpressed in cancer cells. Our results show that 2DG kills cancer cells because, in the process of being reduced by AKR1Bs, depletion of their cofactor NADPH leads to the depletion of glutathione (GSH) and cell death. Furthermore, we showed that compounds that are better substrates for AKR1Bs than 2DG are more effective than 2DG in killing cancer cells that overexpressed these 2 enzymes. As cancer cells can be induced to overexpress AKR1Bs, the anticancer mechanism we identified can be applied to treat a large variety of cancers. This should greatly facilitate the development of novel anticancer drugs.

Original languageEnglish
Pages (from-to)1970-1980
Number of pages11
JournalCancer Science
Volume109
Issue number6
DOIs
Publication statusPublished - Jun 2018

Scopus Subject Areas

  • Oncology
  • Cancer Research

User-Defined Keywords

  • 2-deoxyglucose
  • AKR1B1
  • AKR1B10
  • glutathione (GSH)
  • oxidative stress

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