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

doi:10.1158/0008-5472.CAN-15-2974

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

Cell Biology

Research output: Contribution to journal › Article › peer-review

16 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 language	English (US)
Pages (from-to)	4183-4191
Number of pages	9
Journal	Cancer research
Volume	76
Issue number	14
DOIs	https://doi.org/10.1158/0008-5472.CAN-15-2974
State	Published - Jul 15 2016

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/0008-5472.CAN-15-2974

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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

Zhang, Y, Fox, JT, Park, YU, Elliott, G, Rai, G, Cai, M, Sakamuru, S, Huang, R, Xia, M, Lee, K, Jeon, MH, Mathew, BP, Park, HD, Edelmann, W, Park, CY, Hong, SY, Maloney, D & Myung, K 2016, 'A novel chemotherapeutic agent to treat tumors with DNA mismatch repair deficiencies', Cancer research, vol. 76, no. 14, pp. 4183-4191. https://doi.org/10.1158/0008-5472.CAN-15-2974

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title = "A novel chemotherapeutic agent to treat tumors with DNA mismatch repair deficiencies",

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.",

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

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AU - Cai, Mengli

AU - Sakamuru, Srilatha

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AU - Lee, Kyeryoung

AU - Jeon, Min Ho

AU - Mathew, Bijoy P.

AU - Park, Hee Dong

AU - Edelmann, Winfried

AU - Park, Chan Young

AU - Hong, Sung You

AU - Maloney, David

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N2 - 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.

AB - 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.

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

Abstract

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