Reactive Oxygen Species (ROS) Inducible DNA Cross-Linking Agents and Their Effect on Cancer Cells and Normal Lymphocytes
Reactive Oxygen Species (ROS) Inducible DNA Cross-Linking Agents and Their Effect on Cancer Cells and Normal Lymphocytes
复制标题
活性氧 (ROS) 诱导 DNA 交联剂及其对癌细胞和正常淋巴细胞的影响
DOI：
10.1021/jm401349g
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发表时间：
2014-06-12
影响因子：
7.3
通讯作者：
Peng, Xiaohua
中科院分区：
文献类型：
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作者：
Chen, Wenbing;Balakrishnan, Kumudha;Peng, Xiaohua
降低宿主毒性是癌症化疗的主要挑战之一。许多肿瘤细胞含有高水平的ROS，使它们与正常细胞截然不同。我们报道了一系列ROS激活的芳香氮突变体，它们选择性地杀死慢性淋巴细胞白血病（CLL）而不是正常淋巴细胞。当与H2 O2（癌细胞中最常见的ROS之一）偶联时，这些试剂显示出强大的DNA交联能力，而在没有H2 O2的情况下检测到很少的DNA交联。与化学观察结果一致，体外细胞毒性试验表明，这些药物在从CLL患者分离的原发性白血病淋巴细胞中诱导40-80%的细胞凋亡，但对来自健康供体的正常淋巴细胞的细胞死亡低于25%。在CLL细胞中，最有效的化合物（2）的IC 50为105 μM，而在正常淋巴细胞中未达到IC 50。总的来说，这些数据提供了这些试剂的实用性和选择性，这将激发进一步和有效的应用。
Reducing host toxicity is one of the main challenges of cancer chemotherapy. Many tumor cells contain high levels of ROS that make them distinctively different from normal cells. We report a series of ROS-activated aromatic nitrogen mustards that selectively kill chronic lymphocytic leukemia (CLL) over normal lymphocytes. These agents showed powerful DNA cross-linking abilities when coupled with H2O2, one of the most common ROS in cancer cells, whereas little DNA cross-linking was detected without H2O2. Consistent with chemistry observation, in vitro cytotoxicity assay demonstrated that these agents induced 40–80% apoptosis in primary leukemic lymphocytes isolated from CLL patients but less than 25% cell death to normal lymphocytes from healthy donors. The IC50 for the most potent compound (2) was ∼5 μM in CLL cells, while the IC50 was not achieved in normal lymphocytes. Collectively, these data provide utility and selectivity of these agents that will inspire further and effective applications.