Clioquinol induces DNA double-strand breaks, activation of ATM, and subsequent activation of p53 signaling.
Article Details
- CitationCopy to clipboard
Katsuyama M, Iwata K, Ibi M, Matsuno K, Matsumoto M, Yabe-Nishimura C
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.
- PubMed ID
- 22627294 [ View in PubMed]
- Abstract
Clioquinol, a Cu(2)(+)/Zn(2)(+)/Fe(2)(+) 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 It was eventually withdrawn from the market because of a link to subacute myelo-optic neuropathy (SMON) in Japan.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 GADD45alpha, 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.