Role of NADPH oxidase in arsenic-induced reactive. oxygen species formation and cytotoxicity in myeloid leukemia cells
Role of NADPH oxidase in arsenic-induced reactive. oxygen species formation and cytotoxicity in myeloid leukemia cells
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DOI：
10.1073/pnas.0306687101
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发表时间：
2004-03-30
影响因子：
11.1
通讯作者：
Dang, CV
中科院分区：
文献类型：
--
作者：
Chou, WC;Jie, CF;Dang, CV
几千年来，砷一直在治疗各种疾病方面发挥着关键的药用作用，但在过去的一个世纪里，它的突出地位已经被现代疗法所取代。最近，砷因其治疗急性早幼粒细胞白血病的显著临床疗效而引起人们的注意。尽管暴露于砷的癌细胞中诱导产生的有毒活性氧物种(ROS)可以介导癌细胞死亡，但砷是如何诱导ROS的仍未明确。通过使用基因表达谱、干扰RNA和基因工程细胞，我们在这里报道了NADPH氧化酶，一种正常的白细胞抗菌功能所需的酶复合体，是砷诱导产生ROS的主要靶标。由于NADPH氧化酶活性也可以被佛波酯醋酸酯刺激，因此可以预期砷与临床上使用的佛波酯类似物Bryostatin 1之间通过促进ROS产生的协同作用。我们证明这种协同作用是存在的，并且使用非常低剂量的砷和Bryostatin 1都可以有效地杀死白血病细胞。我们的发现明确了ROS产生的砷靶点，并为抗癌方案提供了概念基础。
Arsenic has played a key medicinal role against a variety of ailments for several millennia, but during the past century its prominence has been displaced by modern therapeutics. Recently, attention has been drawn to arsenic by its dramatic clinical efficacy against acute promyelocytic leukemia. Although toxic reactive oxygen species (ROS) induced in cancer cells exposed to arsenic could mediate cancer cell death, how arsenic induces ROS remains undefined. Through the use of gene expression profiling, interference RNA, and genetically engineered cells, we report here that NADPH oxidase, an enzyme complex required for the normal antibacterial function of white blood cells, is the main target of arsenic-induced ROS production. Because NADPH oxidase enzyme activity can also be stimulated by phorbol myristate acetate, a synergism between arsenic and the clinically used phorbol myristate acetate analog, bryostatin 1, through enhanced ROS production can be expected. We show that this synergism exists, and that the use of very low doses of both arsenic and bryostatin 1 can effectively kill leukemic cells. Our findings pinpoint the arsenic target of ROS production and provide a conceptual basis for an anticancer regimen.