A novel chemotherapeutic agent to treat tumors with DNA mismatch repair deficiencies

Yongliang Zhang, Jennifer T. Fox, Young Un Park, Gene Elliott, Ganesha Rai, Mengli Cai, Srilatha Sakamuru, Ruili Huang, Menghang Xia, Kyeryoung Lee, Min Ho Jeon, Bijoy P. Mathew, Hee Dong Park, Winfried Edelmann, Chan Young Park, Sung You Hong, David Maloney, Kyungjae Myung

Research output: Contribution to journalArticle

7 Scopus citations

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 MutSa-deficient cancer cells. Baicalein binds preferentially to mismatched DNA and induces a DNA damage response in a MMR-dependent manner. In MutSa-proficient cells, baicalein binds to MutSa to dissociate CHK2 from MutSa leading to S-phase arrest and cell survival. In contrast, continued replication in the presence of baicalein in MutSa-deficient cells results in a high number of DNA double-strand breaks and ultimately leads to apoptosis. Consistently, baicalein specifically shrinks MutSa-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.

Original languageEnglish (US)
Pages (from-to)4183-4191
Number of pages9
JournalCancer Research
Volume76
Issue number14
DOIs
StatePublished - Jul 15 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Zhang, Y., Fox, J. T., Park, Y. U., Elliott, G., Rai, G., Cai, M., Sakamuru, S., Huang, R., Xia, M., Lee, K., Jeon, M. H., Mathew, B. P., Park, H. D., Edelmann, W., Park, C. Y., Hong, S. Y., Maloney, D., & Myung, K. (2016). A novel chemotherapeutic agent to treat tumors with DNA mismatch repair deficiencies. Cancer Research, 76(14), 4183-4191. https://doi.org/10.1158/0008-5472.CAN-15-2974