Title |
A Novel Chemotherapeutic Agent to Treat Tumors with DNA Mismatch Repair Deficiencies
|
---|---|
Published in |
Cancer Research, July 2016
|
DOI | 10.1158/0008-5472.can-15-2974 |
Pubmed ID | |
Authors |
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 |
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 mismatch repair-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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
Portugal | 1 | 33% |
United States | 1 | 33% |
Unknown | 1 | 33% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 3 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 42 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 12 | 29% |
Researcher | 7 | 17% |
Student > Master | 4 | 10% |
Student > Bachelor | 3 | 7% |
Student > Doctoral Student | 2 | 5% |
Other | 8 | 19% |
Unknown | 6 | 14% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 13 | 31% |
Agricultural and Biological Sciences | 11 | 26% |
Medicine and Dentistry | 7 | 17% |
Chemistry | 2 | 5% |
Nursing and Health Professions | 1 | 2% |
Other | 2 | 5% |
Unknown | 6 | 14% |