Aldo-keto reductases-mediated cytotoxicity of 2-deoxyglucose: A novel anticancer mechanism
| Autor: | Shi-Qing Zhang, Kin-Lam Yung, Sum-Man Stephen Chung, Sookja K. Chung |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Cancer Research Programmed cell death Cell Survival Mice Nude Antineoplastic Agents Deoxyglucose 03 medical and health sciences chemistry.chemical_compound Aldehyde Reductase Cell Line Tumor Neoplasms Animals Humans Glycolysis Cytotoxicity chemistry.chemical_classification Mice Inbred BALB C Mice Inbred ICR Aldo-Keto Reductase Family 1 member B10 Glucose analog Hep G2 Cells General Medicine Glutathione HCT116 Cells Xenograft Model Antitumor Assays 030104 developmental biology Enzyme Oncology chemistry Cancer cell Cancer research Caco-2 Cells HT29 Cells |
| Zdroj: | Cancer Science. 109:1970-1980 |
| ISSN: | 1347-9032 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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