http://www.ncbi.nlm....les/PMC3325711/
High-throughput genotoxicity assay identifies antioxidants as inducers of DNA damage response and cell death
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.
For example, resveratrol induces breaks in DNA:
First, these compounds were tested for their ability to induce breaks in DNA. Treatment with all compounds increased the fraction of cells having more than 10 chromatid breaks (Fig. 2B and Fig. S5A). Treatment with genistein and resveratrol resulted in a significant induction of a DSB marker, ...
and
N-phenyl-2-napthylamine, daidzein, resveratrol, 2-aminoanthraquinone, and baicalein most likely produce DNA lesions that stall the progression of the replication fork at different levels. This process, in turn, affected the increase in the number of Polη nuclear foci in a similar manner. Even though some previous reports have suggested that polyphenols/antioxidants could produce DNA damage by acting as pro-oxidants, intercalating into DNA, inhibiting topoisomerase, and inhibiting DNA polymerase (Table S3, column 4) (9, 10), the severity of the genotoxicities induced by resveratrol, baicalein, and genistein was surprising. The level of DNA damage caused by a 16-h treatment with 92 μM resveratrol, baicalein, or genistein was comparable to that caused by treatment with the well-known genotoxins MMS and cisplatin
and
We verified that several of these compounds, including resveratrol, genistein, and baicalein, are indeed potent DNA damaging agents at concentrations of 92 μM. Although Western blot analysis did not detect DNA damage responses to concentrations of resveratrol, genistein, and baicalein that could be obtained from oral dosing (2–5 μM) (Fig. S7A) (22, 23), the ATAD5-luc assay identified these compounds as genotoxins at concentrations as low as 2 μM (Fig. S7B). These findings were surprising given that resveratrol and genistein are currently being tested in clinical studies as treatments for cardiovascular disease, type 2 diabetes, osteopenia, and osteoporosis (24, 25); resveratrol has gained notoriety for its potential antiaging effects; and baicalein is the major constituent of a Japanese herbal remedy for chronic hepatitis (26). The genotoxicity caused by these compounds raises concerns regarding their use for such conditions and suggests a reevaluation of their safety.
Another writeup.
http://www.genome.gov/27547858
Edited by viveutvivas, 09 July 2012 - 05:51 PM.
