Oxidative stress-mediated up-regulation of ABC transporters in lung cancer cells
Oxidative stress-mediated up-regulation of ABC transporters in lung cancer cells
复制标题
肺癌细胞中氧化应激介导的 ABC 转运蛋白上调
DOI：
10.1002/jbt.23095
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发表时间：
2022
影响因子：
3.6
通讯作者：
Jian Yin
中科院分区：
文献类型：
--
作者：
Tongkuo Yuan;Jia Hu;Xiaoming Zhu;Huancai Yin;Jian Yin
本文旨在评价氧化应激在人肺癌（A549）细胞面对底物（阿霉素（DOX））和非底物（乙醇（ETH）和过氧化氢（HP））化学物质时ABC转运蛋白调节中的作用。处理24 h后，所有化学品均引起显著的细胞毒性，表现为细胞活力降低和活性氧（ROS）水平升高。根据活性氧清除剂谷胱甘肽（GSH）和维生素C的拯救作用，发现氧化应激的毒性依赖性为HP > ETH > DOX。添加转运蛋白抑制剂显著增强了ROS水平和化学物质的死亡诱导作用，表明ABC转运蛋白具有普遍的解毒功能。在中等ROS水平下（约为对照水平的3-4倍，由10 μM DOX、400 mM ETH和400 μM HP引起），所有三种化学物质均诱导ABC转运蛋白的基因表达和活性，但在LC 50（800 μM）下HP引起的ROS水平过高（为对照水平的8.36倍）时，这些值降低。这种诱导作用可被GSH和KCZ减弱，并可被50 μM KCZ完全消除，表明氧化应激和PXR在ABC转运体的诱导中起重要作用。最后，这篇论文揭示了氧化应激在24小时处理期间通过底物或非底物化学品调节ABC转运蛋白中的关键作用。这些信息应有助于克服ABC转运蛋白介导的多药耐药。
This paper aimed to evaluate the role of oxidative stress in the regulation of ABC transporters in human lung cancer (A549) cells facing substrate (doxorubicin, DOX) and nonsubstrate (ethanol, ETH and hydrogen peroxide, HP) chemicals. After 24‐h treatment, all the chemicals caused significant cytotoxicity as reflected by the reduction in cell viability and the increase in reactive oxygen species (ROS) levels. Depending on the rescuing effects of ROS scavenger including glutathione (GSH) and Vitamin C, the toxicity dependence on oxidative stress were found to be HP > ETH > DOX. The addition of transporter inhibitors significantly enhanced the ROS levels and death‐inducing effects of chemicals, indicating the universal detoxification function of ABC transporters. At moderate ROS levels (about 3–4‐folds of control levels, caused by 10 μM DOX, 400 mM ETH, and 400 μM HP), all the three chemicals induced the gene expressions and activities of ABC transporters, but these values decreased at too high ROS levels (8.36‐folds of control levels) caused by HP at LC50(800 μM). Such induction could be attenuated by GSH and KCZ, and was completely abolished by 50 μM KCZ, indicating an important role of oxidative stress and pregnane X receptor (PXR) in the induction of ABC transporters. Finally, this paper revealed the critical role of oxidative stress in the modulation of ABC transporters by either substrate or nonsubstrate chemicals during 24‐h treatment. Such information should be beneficial for overcoming ABC transporter‐mediated multidrug resistance.