A Novel Chemotherapeutic Agent to Treat Tumors with DNA Mismatch Repair Deficiencies.
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. ©2016 AACR.
Genome Instability Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland.
Yongliang
Y
Zhang
Genome Instability Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland.
Jennifer T
JT
Fox
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.
Young-Un
YU
Park
Transgenic Mouse Core, National Human Genome Research Institute, NIH, Bethesda, Maryland.
Gene
G
Elliott
National Center for Advancing Translational Sciences, NIH, Rockville, Maryland.
Ganesha
G
Rai
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland.
Mengli
M
Cai
National Center for Advancing Translational Sciences, NIH, Rockville, Maryland.
Srilatha
S
Sakamuru
National Center for Advancing Translational Sciences, NIH, Rockville, Maryland.
Ruili
R
Huang
National Center for Advancing Translational Sciences, NIH, Rockville, Maryland.
Menghang
M
Xia
Michael F. Price Center, Albert Einstein College of Medicine, New York, New York.
Kyeryoung
K
Lee
School of Energy and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan, Korea.
Min Ho
MH
Jeon
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.
Bijoy P
BP
Mathew
Institute of Drug Discovery, Research & Development, LG Life Sciences Ltd., Daejeon, Korea.
Hee Dong
HD
Park
Michael F. Price Center, Albert Einstein College of Medicine, New York, New York.
Winfried
W
Edelmann
Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea.
Chan Young
CY
Park
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.
Sung You
SY
Hong
National Center for Advancing Translational Sciences, NIH, Rockville, Maryland.
David
D
Maloney
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.
Kyungjae
K
Myung
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004247:DNA / Q000378:metabolism; D053843:DNA Mismatch Repair; D004268:DNA-Binding Proteins / Q000502:physiology; D044950:Flavanones / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009386:Neoplastic Syndromes, Hereditary / Q000188:drug therapy*
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D044950:Flavanones; C094443:G-T mismatch-binding protein; C006680:baicalein; D004247:DNA; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human