摘要
| 原文 | 英語 |
|---|---|
| 頁（從 - 到） | 996-1005 |
| 頁數 | 10 |
| 期刊 | Molecular Pharmacology |
| 卷 | 87 |
| 發行號 | 6 |
| DOIs | |
| 出版狀態 | 已發佈 - 六月 1 2015 |
指紋
ASJC Scopus subject areas
- Pharmacology
- Molecular Medicine
引用此文
The novel ribonucleotide reductase inhibitor COH29 inhibits DNA repair in vitros. / Chen, Mei Chuan; Zhou, Bingsen; Zhang, Keqiang; Yuan, Yate Ching; Un, Frank; Hu, Shuya; Chou, Chih Ming; Chen, Chun Han; Wu, Jun; Wang, Yan; Liu, Xiyong; Smith, D. Lynne; Li, Hongzhi; Liu, Zheng; Warden, Charles D.; Su, Leila; Malkas, Linda H.; Chung, Young Min; Hu, Mickey C T; Yen, Yun.
於: Molecular Pharmacology, 卷 87, 編號 6, 01.06.2015, p. 996-1005.研究成果: 雜誌貢獻 › 文章
}
TY - JOUR
T1 - The novel ribonucleotide reductase inhibitor COH29 inhibits DNA repair in vitros
AU - Chen, Mei Chuan
AU - Zhou, Bingsen
AU - Zhang, Keqiang
AU - Yuan, Yate Ching
AU - Un, Frank
AU - Hu, Shuya
AU - Chou, Chih Ming
AU - Chen, Chun Han
AU - Wu, Jun
AU - Wang, Yan
AU - Liu, Xiyong
AU - Smith, D. Lynne
AU - Li, Hongzhi
AU - Liu, Zheng
AU - Warden, Charles D.
AU - Su, Leila
AU - Malkas, Linda H.
AU - Chung, Young Min
AU - Hu, Mickey C T
AU - Yen, Yun
PY - 2015/6/1
Y1 - 2015/6/1
N2 - COH29 [N-(4-(3,4-dihydroxyphenyl)-5-phenylthiazol-2-yl)-3,4- dihydroxybenzamide], a novel antimetabolite drug developed at City of Hope Cancer Center, has anticancer activity that stems primarily from the inhibition of human ribonucleotide reductase (RNR). This key enzyme in deoxyribonucleotide biosynthesis is the target of established clinical agents such as hydroxyurea and gemcitabine because of its critical role in DNA replication and repair. Herein we report that BRCA-1-defective human breast cancer cells are more sensitive than wild-type BRCA-1 counterparts to COH29 in vitro and in vivo. Microarray gene expression profiling showed that COH29 reduces the expression of DNA repair pathway genes, suggesting that COH29 interferes with these pathways. It is well established that BRCA1 plays a role in DNA damage repair, especially homologous recombination (HR) repair, to maintain genome integrity. In BRCA1-defective HCC1937 breast cancer cells, COH29 induced more double-strand breaks (DSBs) and DNA-damage response than in HCC1937 + BRCA1 cells. By EJ5- and DR-green fluorescent protein (GFP) reporter assay, we found that COH29 could inhibit nonhomologous end joining (NHEJ) efficiency and that no HR activity was detected in HCC1937 cells, suggesting that repression of the NHEJ repair pathway may be involved in COH29-induced DSBs in BRCA1-deficient HCC1937 cells. Furthermore, we observed an accumulation of nuclear Rad51 foci in COH29-treated HCC1937 + BRCA1 cells, suggesting that BRCA1 plays a crucial role in repairing and recovering drug-induced DNA damage by recruiting Rad51 to damage sites. In summary, we describe here additional biologic effects of the RNR inhibitor COH29 that potentially strengthen its use as an anticancer agent.
AB - COH29 [N-(4-(3,4-dihydroxyphenyl)-5-phenylthiazol-2-yl)-3,4- dihydroxybenzamide], a novel antimetabolite drug developed at City of Hope Cancer Center, has anticancer activity that stems primarily from the inhibition of human ribonucleotide reductase (RNR). This key enzyme in deoxyribonucleotide biosynthesis is the target of established clinical agents such as hydroxyurea and gemcitabine because of its critical role in DNA replication and repair. Herein we report that BRCA-1-defective human breast cancer cells are more sensitive than wild-type BRCA-1 counterparts to COH29 in vitro and in vivo. Microarray gene expression profiling showed that COH29 reduces the expression of DNA repair pathway genes, suggesting that COH29 interferes with these pathways. It is well established that BRCA1 plays a role in DNA damage repair, especially homologous recombination (HR) repair, to maintain genome integrity. In BRCA1-defective HCC1937 breast cancer cells, COH29 induced more double-strand breaks (DSBs) and DNA-damage response than in HCC1937 + BRCA1 cells. By EJ5- and DR-green fluorescent protein (GFP) reporter assay, we found that COH29 could inhibit nonhomologous end joining (NHEJ) efficiency and that no HR activity was detected in HCC1937 cells, suggesting that repression of the NHEJ repair pathway may be involved in COH29-induced DSBs in BRCA1-deficient HCC1937 cells. Furthermore, we observed an accumulation of nuclear Rad51 foci in COH29-treated HCC1937 + BRCA1 cells, suggesting that BRCA1 plays a crucial role in repairing and recovering drug-induced DNA damage by recruiting Rad51 to damage sites. In summary, we describe here additional biologic effects of the RNR inhibitor COH29 that potentially strengthen its use as an anticancer agent.
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UR - http://www.scopus.com/inward/citedby.url?scp=84940054160&partnerID=8YFLogxK
U2 - 10.1124/mol.114.094987
DO - 10.1124/mol.114.094987
M3 - Article
C2 - 25814515
AN - SCOPUS:84940054160
VL - 87
SP - 996
EP - 1005
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 6
ER -