Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
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.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1114278109/-/DCSupplemental.
Freely available online through the PNAS open access option.
High-throughput genotoxicity assay
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