American Association for Cancer Research
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Supplementary Figures from A Novel Chemotherapeutic Agent to Treat Tumors with DNA Mismatch Repair Deficiencies

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posted on 2023-03-31, 00:10 authored by 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

Supplemental Figures contains supplementary figures S1-S13. Supplementary Figure S1. The effect of MSH2 deficiency on cell sensitivity to baicalein. Supplementary Figure S2. Baicalein-treated HEC59 cells are deficient in CHK2-regulated S phase checkpoint arrest. Supplementary Figure S3. Baicalein disrupts the interaction between MutSα and CHK2-ATM. Supplementary Figure S4. Baicalein binds to MutSα. Supplementary Figure S5. Baicalein intercalates DNA but does not form crosslinks. Supplementary Figure S6. XPF deficiency reduces baicalein-induced γ-H2AX and rescues baicalein-induced cell death in HT29 MSH2-deficient cells. Supplementary Figure S7. Baicalein pellets reduce the size of MSH2-deficient xenograft tumors but have little effect on MSH2-proficient tumors. Supplementary Figure S8. Baicalein shrinks MSH2-deficient xenograft tumors in a time-dependent manner. Supplementary Figure S9. Baicalein shrinks xenograft tumors formed by MSH2-deficient LoVo cells. Supplementary Figure S10. Baicalein inhibits the growth of chronic-AOM-DSS-induced colon tumors in Msh2LoxP/LoxPVilCre mice. Supplementary Figure S11. Baicalein inhibits the growth of acute-AOM-DSS-induced colon tumors in Msh2LoxP/LoxPVilCre mice. Supplementary Figure S12. Baicalein have little effect on the growth of chronic-AOM-DSS-induced colon tumors in WT mice. Supplementary Figure S13. Model describing baicalein's mechanism of action.

Funding

National Center for Advancing Translational Sciences

National Human Genome Research Institute

NIH

Institute for Basic Science

History

ARTICLE 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. ©2016 AACR.