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Jin Y, Lu Z, Ding K, Li J, Du X, Chen C, Sun X, Wu Y, Zhou J, Pan J: Antineoplastic mechanisms of niclosamide in acute myelogenous leukemia stem cells: inactivation of the NF-kappaB pathway and generation of reactive oxygen species. Cancer Res. 2010 Mar 15;70(6):2516-27. Epub 2010 Mar 9.
NF-kappaB may be a potential therapeutic target for acute myelogenous leukemia (AML) because NF-kappaB 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-kappaB pathway in AML cells. Niclosamide inhibited the transcription and DNA binding of NF-kappaB. It blocked tumor necrosis factor-induced IkappaBalpha phosphorylation, translocation of p65, and expression of NF-kappaB-regulated genes. Niclosamide inhibited the steps TAK1--> IkappaB kinase (IKK) and IKK--> IkappaBalpha. Niclosamide also increased the levels of reactive oxygen species (ROS) in AML cells. Quenching ROS by the glutathione precursor N-acetylcysteine attenuated niclosamide-induced apoptosis. Our results together suggest that niclosamide inhibited the NF-kappaB 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. |
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