High-throughput genotoxicity assay identifies antioxidants as inducers of DNA damage response and cell death
- aGenome Instability Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, and
- bNational Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892;
- cIntegrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, NC 27711; and
- dDivision of the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709
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Edited by Richard D. Kolodner, Ludwig Institute for Cancer Research, La Jolla, CA, and approved February 16, 2012 (received for review August 30, 2011)

Abstract
Human ATAD5 is a biomarker for identifying genotoxic compounds because ATAD5 protein levels increase posttranscriptionally in response to DNA damage. We screened over 4,000 compounds with a cell-based quantitative high-throughput ATAD5-luciferase assay detecting genotoxic compounds. We identified 22 antioxidants, including resveratrol, genistein, and baicalein, that are currently used or investigated for the treatment of cardiovascular disease, type 2 diabetes, osteopenia, osteoporosis, and chronic hepatitis, as well as for antiaging. Treatment of dividing cells with these compounds induced DNA damage and resulted in cell death. Despite their genotoxic effects, resveratrol, genistein, and baicalein did not cause mutagenesis, which is a major side effect of conventional anticancer drugs. Furthermore, resveratrol and genistein killed multidrug-resistant cancer cells. We therefore propose that resveratrol, genistein, and baicalein are attractive candidates for improved chemotherapeutic agents.
Footnotes
- ↵1To whom correspondence should be addressed. E-mail: kmyung{at}mail.nih.gov.
Author contributions: J.T.F. and K.M. designed research; J.T.F., S.S., R.H., N.T., S.O.S., and K.M. performed research; R.H., S.O.S., M.X., R.R.T., C.P.A., and K.M. contributed new reagents/analytic tools; J.T.F., R.H., M.X., R.R.T., and K.M. analyzed data; and J.T.F. and K.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
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