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High-throughput genotoxicity assay identifies antioxidants as inducers of DNA damage response and cell death

Jennifer T Fox1, Srilatha Sakamuru, Ruili Huang

  • 1Genome Instability Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Proceedings of the National Academy of Sciences of the United States of America
|March 21, 2012
PubMed

Insights

Researchers identified 22 antioxidants, including resveratrol, genistein, and baicalein, that show genotoxic effects but not mutagenesis. These compounds are promising for improved cancer chemotherapy and treating other diseases.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Human ATAD5 protein levels increase posttranscriptionally in response to DNA damage, serving as a biomarker for genotoxic compounds.
  • Genotoxic compounds can cause DNA damage, a critical factor in cancer development and treatment.
  • Existing chemotherapeutic agents often have significant side effects, including mutagenesis.

Purpose of the Study:

  • To screen a large library of compounds for genotoxicity using a novel ATAD5-luciferase assay.
  • To identify novel compounds with potential therapeutic applications, particularly in oncology.
  • To evaluate the safety and efficacy of identified compounds, focusing on genotoxic effects and mutagenesis.

Main Methods:

  • A cell-based, quantitative high-throughput ATAD5-luciferase assay was developed to detect genotoxic compounds.
  • Over 4,000 compounds were screened using this assay.
  • Selected compounds were further tested for their effects on dividing cells, DNA damage, mutagenesis, and multidrug-resistant cancer cells.

Main Results:

  • The screening identified 22 compounds with antioxidant properties, including resveratrol, genistein, and baicalein.
  • These compounds induced DNA damage and cell death in dividing cells.
  • Resveratrol, genistein, and baicalein demonstrated genotoxic effects without causing mutagenesis.
  • Resveratrol and genistein effectively killed multidrug-resistant cancer cells.

Conclusions:

  • Resveratrol, genistein, and baicalein are identified as potent genotoxic agents with a favorable safety profile regarding mutagenesis.
  • These compounds, already investigated for various diseases, show significant potential as improved chemotherapeutic agents.
  • The ATAD5-luciferase assay is a valuable tool for identifying genotoxic compounds with therapeutic potential.

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