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 It was eventually withdrawn from the market because of a link to subacute myelo-optic neuropathy (SMON) in Japan.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: Masato Katsuyama, Kazumi Iwata, Masakazu Ibi, Kuniharu Matsuno, Misaki Matsumoto, Chihiro Yabe-Nishimura
• Journal: Toxicology (Toxicology) Vol. 299 Issue 1 Pg. 55-9 (Sep 04 2012) ISSN: 1879-3185 [Electronic] Ireland
• PMID: 22627294 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• 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

Topics

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