Antineoplastic Mechanisms of Niclosamide in Acute Myelogenous Leukemia Stem Cells: Inactivation of the NF-κB Pathway and Generation of Reactive Oxygen Species
Antineoplastic Mechanisms of Niclosamide in Acute Myelogenous Leukemia Stem Cells: Inactivation of the NF-κB Pathway and Generation of Reactive Oxygen Species
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DOI：
10.1158/0008-5472.can-09-3950
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发表时间：
2010-03-15
期刊：
影响因子：
11.2
通讯作者：
Pan, Jingxuan
中科院分区：
文献类型：
--
作者：
Jin, Yanli;Lu, Zhongzheng;Pan, Jingxuan
NF-κ B可能是急性髓性白血病（AML）的潜在治疗靶点，因为NF-κ B活化存在于原始人AML母细胞中。在这份报告中，我们最初发现，氯硝柳胺，一种食品和药物管理局批准的抗蠕虫药，通过抑制AML细胞中的NF-κ B通路而发挥强效抗蠕虫作用。氯硝柳胺抑制NF-κ B的转录和DNA结合。它阻断肿瘤坏死因子诱导的I κ Ba磷酸化、p65易位和NF-κ B调节基因的表达。氯硝柳胺可抑制IKK 1 → I κ B激酶（IKK）和IKK。我是卡帕巴。氯硝柳胺还增加了AML细胞中活性氧（ROS）的水平。通过谷胱甘肽前体N-乙酰半胱氨酸淬灭ROS可减弱氯硝柳胺诱导的细胞凋亡。我们的研究结果共同表明，氯硝柳胺抑制NF-κ B通路，增加ROS水平，诱导AML细胞凋亡。在氯硝柳胺对AML疗效的转化研究中，氯硝柳胺杀死了AML患者的祖细胞/干细胞，但保留了正常骨髓中的祖细胞/干细胞。氯硝柳胺与一线化疗药物阿糖胞苷、依托泊苷和柔红霉素具有协同作用。它在体外和裸鼠中有效地抑制AML细胞的生长。我们的结果支持氯硝柳胺在AML患者的临床试验中的进一步研究。Cancer Res; 70（6）; 2516-27.（C）2010年AACR。
NF-kappa B may be a potential therapeutic target for acute myelogenous leukemia (AML) because NF-kappa B activation is found in primitive human AML blast cells. In this report, we initially discovered that the potent antineoplastic effect of niclosamide, a Food and Drug Administration-approved antihelminthic agent, was through inhibition of the NF-kappa B pathway in AML cells. Niclosamide inhibited the transcription and DNA binding of NF-kappa B. It blocked tumor necrosis factor-induced I kappa Ba phosphorylation, translocation of p65, and expression of NF-kappa B-regulated genes. Niclosamide inhibited the steps TAK1 -> I kappa B kinase (IKK) and IKK. I kappa Ba. Niclosamide also increased the levels of reactive oxygen species (ROS) inAML cells. Quenching ROS by the glutathione precursor N-acetylcysteine attenuated niclosamide-induced apoptosis. Our results together suggest that niclosamide inhibited the NF-kappa B pathway and increased ROS levels to induce apoptosis in AML cells. On translational study of the efficacy of niclosamide against AML, niclosamide killed progenitor/stem cells from AML patients but spared those from normal bone marrow. Niclosamide was synergistic with the frontline chemotherapeutic agents cytarabine, etoposide, and daunorubicin. It potently inhibited the growth of AML cells in vitro and in nude mice. Our results support further investigation of niclosamide in clinical trials of AML patients. Cancer Res; 70(6); 2516-27. (C)2010 AACR.