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Cancer Res. 2016 Jul 15;76(14):4183-91. doi: 10.1158/0008-5472.CAN-15-2974. Epub 2016 Jun 4.

A Novel Chemotherapeutic Agent to Treat Tumors with DNA Mismatch Repair Deficiencies.

Author information

1
Genome Instability Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland.
2
Center for Genomic Integrity, Institute for Basic Science, Ulsan, Korea. Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea.
3
Transgenic Mouse Core, National Human Genome Research Institute, NIH, Bethesda, Maryland.
4
National Center for Advancing Translational Sciences, NIH, Rockville, Maryland.
5
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland.
6
Michael F. Price Center, Albert Einstein College of Medicine, New York, New York.
7
School of Energy and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan, Korea.
8
Center for Genomic Integrity, Institute for Basic Science, Ulsan, Korea. School of Energy and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan, Korea.
9
Institute of Drug Discovery, Research & Development, LG Life Sciences Ltd., Daejeon, Korea.
10
Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea.
11
Genome Instability Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland. Center for Genomic Integrity, Institute for Basic Science, Ulsan, Korea. Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea. kmyung@ibs.re.kr.

Abstract

Impairing the division of cancer cells with genotoxic small molecules has been a primary goal to develop chemotherapeutic agents. However, DNA mismatch repair (MMR)-deficient cancer cells are resistant to most conventional chemotherapeutic agents. Here we have identified baicalein as a small molecule that selectively kills MutSα-deficient cancer cells. Baicalein binds preferentially to mismatched DNA and induces a DNA damage response in a MMR-dependent manner. In MutSα-proficient cells, baicalein binds to MutSα to dissociate CHK2 from MutSα leading to S-phase arrest and cell survival. In contrast, continued replication in the presence of baicalein in MutSα-deficient cells results in a high number of DNA double-strand breaks and ultimately leads to apoptosis. Consistently, baicalein specifically shrinks MutSα-deficient xenograft tumors and inhibits the growth of AOM-DSS-induced colon tumors in colon-specific MSH2 knockout mice. Collectively, baicalein offers the potential of an improved treatment option for patients with tumors with a DNA MMR deficiency. Cancer Res; 76(14); 4183-91.

PMID:
27262172
PMCID:
PMC5033673
DOI:
10.1158/0008-5472.CAN-15-2974
[Indexed for MEDLINE]
Free PMC Article

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