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, Kye-Ryoung 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

4 Citations (Scopus)

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

Fingerprint

DNA Repair-Deficiency Disorders
DNA Mismatch Repair
Neoplasms
Colon
Double-Stranded DNA Breaks
S Phase
Heterografts
Knockout Mice
Cell Division
DNA Damage
Turcot syndrome
baicalein
Cell Survival
Apoptosis
DNA
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Zhang, Y., Fox, J. T., Park, Y. U., Elliott, G., Rai, G., Cai, M., ... 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

A novel chemotherapeutic agent to treat tumors with DNA mismatch repair deficiencies. / Zhang, Yongliang; Fox, Jennifer T.; Park, Young Un; Elliott, Gene; Rai, Ganesha; Cai, Mengli; Sakamuru, Srilatha; Huang, Ruili; Xia, Menghang; Lee, Kye-Ryoung; Jeon, Min Ho; Mathew, Bijoy P.; Park, Hee Dong; Edelmann, Winfried; Park, Chan Young; Hong, Sung You; Maloney, David; Myung, Kyungjae.

In: Cancer Research, Vol. 76, No. 14, 15.07.2016, p. 4183-4191.

Research output: Contribution to journalArticle

Zhang, Y, Fox, JT, Park, YU, Elliott, G, Rai, G, Cai, M, Sakamuru, S, Huang, R, Xia, M, Lee, K-R, 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
Zhang, Yongliang ; Fox, Jennifer T. ; Park, Young Un ; Elliott, Gene ; Rai, Ganesha ; Cai, Mengli ; Sakamuru, Srilatha ; Huang, Ruili ; Xia, Menghang ; Lee, Kye-Ryoung ; Jeon, Min Ho ; Mathew, Bijoy P. ; Park, Hee Dong ; Edelmann, Winfried ; Park, Chan Young ; Hong, Sung You ; Maloney, David ; Myung, Kyungjae. / A novel chemotherapeutic agent to treat tumors with DNA mismatch repair deficiencies. In: Cancer Research. 2016 ; Vol. 76, No. 14. pp. 4183-4191.
@article{c88d056a29704310a60ad4f43f662cde,
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 Kye-Ryoung 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",
year = "2016",
month = "7",
day = "15",
doi = "10.1158/0008-5472.CAN-15-2974",
language = "English (US)",
volume = "76",
pages = "4183--4191",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "14",

}

TY - JOUR

T1 - A novel chemotherapeutic agent to treat tumors with DNA mismatch repair deficiencies

AU - Zhang, Yongliang

AU - Fox, Jennifer T.

AU - Park, Young Un

AU - Elliott, Gene

AU - Rai, Ganesha

AU - Cai, Mengli

AU - Sakamuru, Srilatha

AU - Huang, Ruili

AU - Xia, Menghang

AU - Lee, Kye-Ryoung

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

AU - Myung, Kyungjae

PY - 2016/7/15

Y1 - 2016/7/15

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.

UR - http://www.scopus.com/inward/record.url?scp=84978419126&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84978419126&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-15-2974

DO - 10.1158/0008-5472.CAN-15-2974

M3 - Article

C2 - 27262172

AN - SCOPUS:84978419126

VL - 76

SP - 4183

EP - 4191

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 14

ER -