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

被引：102

作者：

Fox, Jennifer T. ^{[1
]}

Sakamuru, Srilatha ^{[2
]}

Huang, Ruili ^{[2
]}

Teneva, Nedelina ^{[1
]}

Simmons, Steven O. ^{[3
]}

Xia, Menghang ^{[2
]}

Tice, Raymond R. ^{[4
]}

Austin, Christopher P. ^{[2
]}

Myung, Kyungjae ^{[1
]}

机构：

[1] NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, Bethesda, MD 20892 USA

[2] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA

[3] US EPA, Integrated Syst Toxicol Div, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA

[4] NIEHS, Div Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2012年 / 109卷 / 14期

基金：

美国国家卫生研究院;

关键词：

chemotherapy; high-throughput screening; POSTMENOPAUSAL WOMEN; PHYTOESTROGEN GENISTEIN; XERODERMA-PIGMENTOSUM; CHEMICAL LIBRARIES; POLYMERASE ETA; CANCER CELLS; HUMAN ELG1; NUDE-MICE; IN-VIVO; RESVERATROL;

D O I：

10.1073/pnas.1114278109

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

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.

引用

页码：5423 / 5428

页数：6

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