Discovery of small-molecule enhancers of reactive oxygen species that are nontoxic or cause genotype-selective cell death.
Discovery of small-molecule enhancers of reactive oxygen species that are nontoxic or cause genotype-selective cell death.
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DOI：
10.1021/cb300653v
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发表时间：
2013-05-17
影响因子：
4
通讯作者：
Schreiber, Stuart L.
中科院分区：
文献类型：
--
作者：
Adams, Drew J.;Boskovic, Zarko V.;Theriault, Jimmy R.;Wang, Alex J.;Stern, Andrew M.;Wagner, Bridget K.;Shamji, Alykhan F.;Schreiber, Stuart L.
相对于非转化细胞，在许多癌细胞中观察到活性氧（ROS）水平升高，最近的报告表明，ROS的小分子增强剂可以在各种体外和体内模型中选择性地杀死癌细胞。我们使用高通量筛选方法在人骨肉瘤细胞系中鉴定了数百种ROS的小分子增强剂。这些化合物中的少数降低了癌细胞系的活力，表明小分子引起的ROS升高不足以诱导癌细胞系的死亡。三种化学探针（BRD 5459、BRD 56491、BRD 9092）被突出显示，其最强烈地升高氧化应激的标志物而不引起细胞死亡，并且可用于各种细胞环境。例如，将无毒的ROS增强探针与无毒剂量的l-丁硫氨酸亚砜亚胺（一种先前在癌症患者中研究的谷胱甘肽合成抑制剂）相结合，导致20多个病例中的有效细胞死亡，这表明即使是无毒的ROS增强治疗也可能需要探索组合策略。此外，在肿瘤发生的工程细胞系模型中，一些含有亲电性位点的ROS增强化合物（包括piperlongumine）对转化细胞的选择性毒性超过非转化细胞。这些研究表明，癌细胞系对化学诱导的ROS水平增加的适应性比以前认为的更强，并强调亲电性是一种可能比ROS升高与癌症选择性细胞死亡更密切相关的性质。
Elevation of reactive oxygen species (ROS) levels has been observed in many cancer cells relative to nontransformed cells, and recent reports have suggested that small-molecule enhancers of ROS may selectively kill cancer cells in various in vitro and in vivo models. We used a high-throughput screening approach to identify several hundred small-molecule enhancers of ROS in a human osteosarcoma cell line. A minority of these compounds diminished the viability of cancer cell lines, indicating that ROS elevation by small molecules is insufficient to induce death of cancer cell lines. Three chemical probes (BRD5459, BRD56491, BRD9092) are highlighted that most strongly elevate markers of oxidative stress without causing cell death and may be of use in a variety of cellular settings. For example, combining nontoxic ROS-enhancing probes with nontoxic doses of l-buthionine sulfoximine, an inhibitor of glutathione synthesis previously studied in cancer patients, led to potent cell death in more than 20 cases, suggesting that even nontoxic ROS-enhancing treatments may warrant exploration in combination strategies. Additionally, a few ROS-enhancing compounds that contain sites of electrophilicity, including piperlongumine, show selective toxicity for transformed cells over nontransformed cells in an engineered cell-line model of tumorigenesis. These studies suggest that cancer cell lines are more resilient to chemically induced increases in ROS levels than previously thought and highlight electrophilicity as a property that may be more closely associated with cancer-selective cell death than ROS elevation.
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影响因子：
4.8
作者：
Lee, AC;Fenster, BE;Finkel, T
通讯作者：
Finkel, T
影响因子：
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作者：
Hur, Wooyoung;Sun, Zheng;Gray, Nathanael S.
通讯作者：
Gray, Nathanael S.
影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Hahn, WC
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作者：
Watson J
通讯作者：
Watson J