Open AccessAldo‐keto reductases‐mediated cytotoxicity of 2‐deoxyglucose: A novel anticancer mechanism
Author(s) -
Zhang ShiQing,
Yung KinLam Ken,
Chung Sookja Kim,
Chung SumMan Stephen
Publication year - 2018
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13604
Subject(s) - cancer cell , cancer , cancer research , glutathione , cytotoxicity , glycolysis , enzyme , chemotherapy , biochemistry , biology , chemistry , in vitro , genetics
2‐Deoxyglucose (2 DG ) 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 2 DG in cancer cells is mediated by the enzymatic activities of AKR 1B1 and/or AKR 1B10 ( AKR 1Bs), which are often overexpressed in cancer cells. Our results show that 2 DG kills cancer cells because, in the process of being reduced by AKR 1Bs, 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 AKR 1Bs than 2 DG are more effective than 2 DG in killing cancer cells that overexpressed these 2 enzymes. As cancer cells can be induced to overexpress AKR 1Bs, 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.