title: High-throughput genotoxicity assay identifies antioxidants as inducers of DNA damage response and cell death.
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.
authors.affiliation: Genome Instability Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jennifer T
authors.initials: JT
authors.lastname: Fox
authors.forename: Srilatha
authors.initials: S
authors.lastname: Sakamuru
authors.forename: Ruili
authors.initials: R
authors.lastname: Huang
authors.forename: Nedelina
authors.initials: N
authors.lastname: Teneva
authors.forename: Steven O
authors.initials: SO
authors.lastname: Simmons
authors.forename: Menghang
authors.initials: M
authors.lastname: Xia
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Tice
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
authors.forename: Kyungjae
authors.initials: K
authors.lastname: Myung
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D004249:DNA Damage; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D044950:Flavanones / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D009152:Mutagenicity Tests; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D044950:Flavanones; D013267:Stilbenes; C006680:baicalein; D019833:Genistein; D000077185:Resveratrol