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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >High-throughput genotoxicity assay identifies antioxidants as inducers of DNA damage response and cell death
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High-throughput genotoxicity assay identifies antioxidants as inducers of DNA damage response and cell death

机译:高通量遗传毒性测定可确定抗氧化剂是DNA损伤反应和细胞死亡的诱因

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摘要

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.
机译:人ATAD5是鉴定遗传毒性化合物的生物标记,因为ATAD5蛋白水平在转录后响应DNA损伤而增加。我们使用基于细胞的定量高通量ATAD5-荧光素酶测定法筛选了4,000多种化合物,检测了遗传毒性化合物。我们确定了22种抗氧化剂,包括白藜芦醇,染料木黄酮和黄ical素,这些抗氧化剂目前用于治疗心血管疾病,2型糖尿病,骨质减少,骨质疏松和慢性肝炎以及抗衰老。用这些化合物处理分裂细胞会诱导DNA损伤,并导致细胞死亡。尽管白藜芦醇,染料木黄酮和黄ba素具有遗传毒性作用,但它们并未引起诱变,这是常规抗癌药物的主要副作用。此外,白藜芦醇和染料木黄酮杀死了多药耐药癌细胞。因此,我们提出白藜芦醇,金雀异黄素和黄e素是改良化学治疗剂的有吸引力的候选者。

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  • 作者单位

    Genome Instability Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, and National Institutes of Health, Bethesda, MD 20892;

    National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892;

    National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892;

    Genome Instability Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, and National Institutes of Health, Bethesda, MD 20892;

    Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, NC 27711;

    National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892;

    Division of the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;

    National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892;

    Genome Instability Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, and National Institutes of Health, Bethesda, MD 20892;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    chemotherapy; high-thfoughput screening;

    机译:化学疗法高通量筛选;

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