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      The antiparasitic clioquinol induces apoptosis in leukemia and myeloma cells by inhibiting histone deacetylase activity.

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          Abstract

          The antiparasitic clioquinol (CQ) represents a class of novel anticancer drugs by interfering with proteasome activity. In the present study, we found that CQ induced blood cancer cell apoptosis by inhibiting histone deacetylases (HDACs). CQ accumulated the acetylation levels of several key proteins including histone H3 (H3), p53, HSP90, and α-tubulin. In the mechanistic study, CQ was found to down-regulate HDAC1, -3, -4, and -5 in both myeloma and leukemia cells. Computer modeling analysis revealed that CQ was well docked into the active pocket of the enzyme, where the oxygen and nitrogen atoms in CQ formed stable coordinate bonds with the zinc ion, and the hydroxyl group from CQ formed an effective hydrogen bond with Asp-267. Moreover, co-treatment with CQ and zinc/copper chloride led to decreased Ac-H3. Furthermore, CQ inhibited the activity of Class I and IIa HDACs in the cell-free assays, demonstrating that CQ interfered with HDAC activity. By inhibiting HDAC activity, CQ induced expression of p21, p27, and p53, cell cycle arrest at G1 phase, and cell apoptosis. This study suggested that the HDAC enzymes are targets of CQ, which provided a novel insight into the molecular mechanism of CQ in the treatment of hematological malignancies.

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          Author and article information

          Journal
          J. Biol. Chem.
          The Journal of biological chemistry
          1083-351X
          0021-9258
          Nov 22 2013
          : 288
          : 47
          Affiliations
          [1 ] From the Cyrus Tang Hematology Center.
          Article
          M113.472563
          10.1074/jbc.M113.472563
          3837159
          24114842
          5f6a5e01-c664-49ef-a0a7-fba75c4252ef
          History

          Apoptosis,Clioquinol,Computer Modeling,Enzyme Inhibitors,Histone Deacetylase,Multiple Myeloma

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