title: Clioquinol induces DNA double-strand breaks, activation of ATM, and subsequent activation of p53 signaling.
abstract: Clioquinol, a Cu²⁺/Zn²⁺/Fe²⁺ chelator/ionophor, was used extensively in the mid 1900s as an amebicide for treating indigestion and diarrhea. It was eventually withdrawn from the market because of a link to subacute myelo-optic neuropathy (SMON) in Japan. The pathogenesis of SMON, however, is not fully understood. To clarify the molecular mechanisms of clioquinol-induced neurotoxicity, a global analysis using DNA chips was carried out on human neuroblastoma cells. The global analysis and quantitative PCR demonstrated that mRNA levels of p21(Cip1), an inhibitor of cyclins D and E, and of GADD45α, a growth arrest and DNA damage-inducible protein, were significantly increased by clioquinol treatment in SH-SY5Y and IMR-32 neuroblastoma cells. Activation of p53 by clioquinol was suggested, since clioquinol induced phosphorylation of p53 at Ser15 to enhance its stabilization. The phosphorylation of p53 was inhibited by KU-55933, an inhibitor of ataxia-telangiectasia mutated kinase (ATM), but not by NU7026, an inhibitor of DNA-dependent protein kinase (DNA-PK). Clioquinol in fact induced phosphorylation of ATM and histone H2AX, a marker of DNA double-strand breaks (DSBs). These results suggest that clioquinol-induced neurotoxicity is mediated by DSBs and subsequent activation of ATM/p53 signaling.
authors.affiliation: Radioisotope Center, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan. mkatsuya@koto.kpu-m.ac.jp
authors.forename: Masato
authors.initials: M
authors.lastname: Katsuyama
authors.forename: Kazumi
authors.initials: K
authors.lastname: Iwata
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ibi
authors.forename: Kuniharu
authors.initials: K
authors.lastname: Matsuno
authors.forename: Misaki
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yabe-Nishimura
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D007464:Clioquinol / Q000633:toxicity*; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009447:Neuroblastoma; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011753:Pyrones / Q000494:pharmacology; D012313:RNA / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C479235:2-(morpholin-4-yl)benzo(h)chromen-4-one; C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D018797:Cell Cycle Proteins; D002867:Chromones; D004268:DNA-Binding Proteins; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011753:Pyrones; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D012313:RNA; D007464:Clioquinol; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases