Department of Biology, Hong Kong Baptist University, Hong Kong, China.
Division of Science and Technology, United International College, Zhuhai, China.
Cancer Sci. 2018 Jun;109(6):1970-1980. doi: 10.1111/cas.13604. Epub 2018 May 3.
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.
2-脱氧葡萄糖（2DG）是一种不可代谢的葡萄糖类似物，目前正在临床试验中，以确定其在增强几种类型癌症的放疗和化疗疗效方面的功效。人们认为它通过抑制糖酵解来优先杀死癌细胞，因为癌细胞比正常细胞更依赖糖酵解来满足其能量需求。然而，我们发现 2DG 在癌细胞中的毒性是由 AKR1B1 和/或 AKR1B10（AKR1Bs）的酶活性介导的，这些酶在癌细胞中常常过度表达。我们的结果表明，2DG 杀死癌细胞是因为在被 AKR1Bs 还原的过程中，其辅因子 NADPH 的耗竭导致谷胱甘肽（GSH）的耗竭和细胞死亡。此外，我们表明，比 2DG 更适合 AKR1Bs 的化合物在杀死过度表达这两种酶的癌细胞方面比 2DG 更有效。由于癌细胞可以被诱导过度表达 AKR1Bs，因此我们确定的抗癌机制可以应用于治疗多种癌症。这将极大地促进新型抗癌药物的开发。
