Aldo-keto reductase inhibitors increase the anticancer effects of tyrosine kinase inhibitors in chronic myelogenous leukemia
Aldo-keto reductase inhibitors increase the anticancer effects of tyrosine kinase inhibitors in chronic myelogenous leukemia
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醛酮还原酶抑制剂增强酪氨酸激酶抑制剂对慢性粒细胞白血病的抗癌作用
DOI：
10.1016/j.jphs.2021.05.001
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发表时间：
2021
影响因子：
3.5
通讯作者：
Shigeki Aoki
中科院分区：
文献类型：
--
作者：
Megumi Kikuya;Kenta Furuichi;Takuya Hirao;Satoshi Endo;Naoki Toyooka;Kousei Ito;Shigeki Aoki
酪氨酸激酶抑制剂（TKI）在临床实践中被广泛用于治疗癌症，但慢性治疗期间的继发性肿瘤耐药性可能存在问题。醛酮还原酶（AKR）超家族的AKR 1B 1和AKR 1B 10在癌细胞中高度表达，并被认为与耐药性有关。本研究的目的是了解TKI治疗慢性粒细胞白血病（CML）细胞如何改变其葡萄糖代谢，以及抑制AKR是否可以使CML细胞对TKI敏感。用TKI伊马替尼、尼洛替尼或博舒替尼处理K562细胞，并评估对葡萄糖代谢、细胞死亡、谷胱甘肽水平和AKR水平的影响。为了评估葡萄糖依赖性，在正常和低葡萄糖培养基中培养细胞。使用AKR抑制剂（包括依帕司他）进行预处理，以确定AKR依赖性。TKI治疗增加了细胞内葡萄糖、AKR 1B 1/10水平、谷胱甘肽氧化和核因子红细胞2相关因子2的核转位，但细胞死亡极少。这些作用依赖于细胞内葡萄糖的积累。用依帕司他或AKR 1B 10的选择性抑制剂预处理，加剧了TKI诱导的细胞死亡，这表明AKR 1B 10尤其参与了对TKI的保护。因此，通过破坏细胞保护机制，AKR抑制剂可能使CML对TKI治疗更敏感。
Tyrosine kinase inhibitors (TKIs) are widely utilized in clinical practice to treat carcinomas, but secondary tumor resistance during chronic treatment can be problematic. AKR1B1 and AKR1B10 of the aldo-keto reductase (AKR) superfamily are highly expressed in cancer cells and are believed to be involved in drug resistance. The aim of this study was to understand how TKI treatment of chronic myelogenous leukemia (CML) cells changes their glucose metabolism and if inhibition of AKRs can sensitize CML cells to TKIs. K562 cells were treated with the TKIs imatinib, nilotinib, or bosutinib, and the effects on glucose metabolism, cell death, glutathione levels, and AKR levels were assessed. To assess glucose dependence, cells were cultured in normal and low-glucose media. Pretreatment with AKR inhibitors, including epalrestat, were used to determine AKR-dependence. Treatment with TKIs increased intracellular glucose, AKR1B1/10 levels, glutathione oxidation, and nuclear translocation of nuclear factor erythroid 2-related factor 2, but with minimal cell death. These effects were dependent on intracellular glucose accumulation. Pretreatment with epalrestat, or a selective inhibitor of AKR1B10, exacerbated TKI-induced cell death, suggesting that especially AKR1B10 was involved in protection against TKIs. Thus, by disrupting cell protective mechanisms, AKR inhibitors may render CML more susceptible to TKI treatments.