RT Journal Article
SR Electronic
T1 The Novel Ribonucleotide Reductase Inhibitor COH29 Inhibits DNA Repair In Vitro
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.114.094987
DO 10.1124/mol.114.094987
A1 Mei-Chuan Chen
A1 Bingsen Zhou
A1 Keqiang Zhang
A1 Yate-Ching Yuan
A1 Frank Un
A1 Shuya Hu
A1 Chih-Ming Chou
A1 Chun-Han Chen
A1 Jun Wu
A1 Yan Wang
A1 Xiyong Liu
A1 Lynne Smith
A1 Charles D Warden
A1 Zheng Liu
A1 Hongzhi Li
A1 Leila Su
A1 Linda H Malkas
A1 Young Min Chung
A1 Mickey C-T Hu
A1 Yun Yen
YR 2015
UL http://molpharm.aspetjournals.org/content/early/2015/03/26/mol.114.094987.abstract
AB COH29, 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 (HU) 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 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 (DSB) and DNA-damage response (DDR) than in HCC1937+BRCA1 cells. By EJ5- and DR-GFP reporter assay, we found COH29 could inhibit NHEJ efficiency and that no HR activity was detected in HCC1937 cells, suggesting the repression of the NHEJ repair pathway may be involved in COH29-induced DSB in BRCA1-deficient HCC1937 cells. Furthermore, we observed accumulation of nuclear Rad51 foci in COH29-treated HCC1937+BRCA1 cells, suggesting BRCA1 plays a crucial role in repairing/recovering drug-induced DNA damage by recruiting Rad51 to damage sites. In summary, we have described additional biological effects of the RNR inhibitor COH29 that potentially strengthen its utility as an anticancer agent.