Clioquinol induces DNA double-strand breaks, activation of ATM, and subsequent activation of p53 signaling

Masato Katsuyama; Kazumi Iwata; Masakazu Ibi; Kuniharu Matsuno; Misaki Matsumoto; Chihiro Yabe-Nishimura

doi:10.1016/j.tox.2012.05.013

Clioquinol induces DNA double-strand breaks, activation of ATM, and subsequent activation of p53 signaling

Toxicology. 2012 Sep 4;299(1):55-9. doi: 10.1016/j.tox.2012.05.013. Epub 2012 May 22.

Authors

Masato Katsuyama¹, Kazumi Iwata, Masakazu Ibi, Kuniharu Matsuno, Misaki Matsumoto, Chihiro Yabe-Nishimura

Affiliation

¹ Radioisotope Center, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan. mkatsuya@koto.kpu-m.ac.jp

PMID: 22627294
DOI: 10.1016/j.tox.2012.05.013

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 It was eventually withdrawn from the market because of a link to subacute myelo-optic neuropathy (SMON) in Japan.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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Ataxia Telangiectasia Mutated Proteins
Blotting, Western
Cell Cycle Proteins / antagonists & inhibitors
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism*
Cell Line, Tumor
Chromones / pharmacology
Clioquinol / toxicity*
DNA Breaks, Double-Stranded*
DNA-Binding Proteins / antagonists & inhibitors
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Humans
Morpholines / pharmacology
Neuroblastoma
Neurotoxicity Syndromes / etiology*
Neurotoxicity Syndromes / metabolism
Phosphorylation / drug effects
Protein Kinase Inhibitors / pharmacology
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Pyrones / pharmacology
RNA / chemistry
RNA / genetics
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / drug effects*
Tumor Suppressor Protein p53 / antagonists & inhibitors
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism*
Tumor Suppressor Proteins / antagonists & inhibitors
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*

Substances

2-(morpholin-4-yl)benzo(h)chromen-4-one
2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one
Cell Cycle Proteins
Chromones
DNA-Binding Proteins
Morpholines
Protein Kinase Inhibitors
Pyrones
TP53 protein, human
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
RNA
Clioquinol
ATM protein, human
Ataxia Telangiectasia Mutated Proteins
Protein Serine-Threonine Kinases