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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.

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.

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This file has methods used in the study in addition to methods described in the manuscript.

This file has detail figure legends for supplementary figures.