Selective leukemic-cell killing by a novel functional class of thalidomide analogs
Selective leukemic-cell killing by a novel functional class of thalidomide analogs
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DOI：
10.1182/blood-2006-04-017046
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发表时间：
2006-12-15
期刊：
影响因子：
20.3
通讯作者：
Gardner, Kevin
中科院分区：
文献类型：
--
作者：
Ge, Yun;Montano, Idalia;Gardner, Kevin
使用一种新的基于细胞的分析转录途径靶向，我们已经确定了一个新的功能类沙利度胺类似物具有独特的和选择性的抗白血病活性。这些药物激活活化T细胞的核因子（NFAT）转录途径，同时通过细胞内活性氧（ROS）的快速扩增抑制核因子- kb （NF-KB）。ROS升高与细胞内游离钙增加、线粒体膜电位快速耗散、线粒体结构破坏和不依赖caspase的细胞死亡有关。这种细胞毒性对转化淋巴细胞具有高度选择性，可被自由基清除剂逆转，与其他氧化还原化合物的抗白血病活性协同作用，并优先靶向细胞周期S期的细胞。活细胞成像显示，在扩散到整个细胞之前，药物诱导的ROS起源于内质网和相关的线粒体。为成员;作为一类新型功能的“氧化还原反应性”沙利度胺，这些化合物提供了一种新的工具，通过合理的组合治疗策略和适当的药物设计，可以利用氧化还原状态和细胞内生物活化的选择性细胞特性，以利用细胞特异性脆弱性获得最大的药物功效。（Blood. 2006;108:4126-4135）(c) 2006年由美国血液学会出版。
Using a novel cell-based assay to profile transcriptional pathway targeting, we have identified a new functional class of thalidomide analogs with distinct and selective antileukemic activity. These agents activate nuclear factor of activated T cells (NFAT) transcriptional pathways while simultaneously repressing nuclear factor-KB (NF-KB) via a rapid intracellular amplification of reactive oxygen species (ROS). The elevated ROS is associated with increased intracellular free calcium, rapid dissipation of the mitochondrial membrane potential, disrupted mitochondrial structure, and caspase-independent cell death. This cytotoxicity is highly selective for transformed lymphoid cells, is reversed by free radical scavengers, synergizes with the antileukemic activity of other redox-directed compounds, and preferentially targets cells in the S phase of the cell cycle. Live-cell imaging reveals a rapid drug-induced burst of ROS originating in the endoplasmic reticulum and associated mitochondria just prior to spreading throughout the cell. As members; of a novel functional class of "redox-reactive" thalidomides, these compounds provide a new tool through which selective cellular properties of redox status and intracellular bioactivation can be leveraged by rational combinatorial therapeutic strategies and appropriate drug design to exploit cell-specific vulnerabilities for maximum drug efficacy. (Blood. 2006;108:4126-4135)(c) 2006 by The American Society of Hematology.