title: The antiparasitic clioquinol induces apoptosis in leukemia and myeloma cells by inhibiting histone deacetylase activity.
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.
authors.affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou, China 215123.
authors.forename: Biyin
authors.initials: B
authors.lastname: Cao
authors.affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou, China 215123.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou, China 215123.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Institute of Functional Nano & Soft Materials, Soochow University, Suzhou, China 215123.
authors.forename: Mingyun
authors.initials: M
authors.lastname: Shen
authors.affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou, China 215123.
authors.forename: Kunkun
authors.initials: K
authors.lastname: Han
authors.affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou, China 215123.
authors.forename: Zubin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Pharmacy School, Soochow University, Suzhou, China 215123.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou, China 215123.
authors.forename: Yali
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Suzhou, China 215006.
authors.forename: Depei
authors.initials: D
authors.lastname: Wu
authors.affiliation: Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Suzhou, China 215006.
authors.forename: Suning
authors.initials: S
authors.lastname: Chen
authors.affiliation: Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Suzhou, China 215006.
authors.forename: Aining
authors.initials: A
authors.lastname: Sun
authors.affiliation: Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Suzhou, China 215006.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Tang
authors.affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou, China 215123.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, Pharmacy School, Soochow University, Suzhou, China 215123.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Qiao
authors.affiliation: Institute of Functional Nano & Soft Materials, Soochow University, Suzhou, China 215123.
authors.forename: Tingjun
authors.initials: T
authors.lastname: Hou
authors.affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou, China 215123; Department of Pharmacology, Pharmacy School, Soochow University, Suzhou, China 215123. Electronic address: xinliangmao@suda.edu.cn.
authors.forename: Xinliang
authors.initials: X
authors.lastname: Mao
mesh_terms: D000982:Antipruritics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002712:Chlorides / Q000494:pharmacology; D007464:Clioquinol / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D009067:Mouthwashes / Q000494:pharmacology; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020298:U937 Cells; D017967:Zinc Compounds / Q000494:pharmacology
chemical_list: D000982:Antipruritics; D002712:Chlorides; D056572:Histone Deacetylase Inhibitors; D009067:Mouthwashes; D009363:Neoplasm Proteins; D017967:Zinc Compounds; D007464:Clioquinol; C016837:zinc chloride; D006655:Histone Deacetylases
keywords: Apoptosis; Clioquinol; Computer Modeling; Enzyme Inhibitors; Histone Deacetylase; Multiple Myeloma