TY - JOUR T1 - The Novel Ribonucleotide Reductase Inhibitor COH29 Inhibits DNA Repair In Vitro JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.114.094987 SP - mol.114.094987 AU - Mei-Chuan Chen AU - Bingsen Zhou AU - Keqiang Zhang AU - Yate-Ching Yuan AU - Frank Un AU - Shuya Hu AU - Chih-Ming Chou AU - Chun-Han Chen AU - Jun Wu AU - Yan Wang AU - Xiyong Liu AU - Lynne Smith AU - Charles D Warden AU - Zheng Liu AU - Hongzhi Li AU - Leila Su AU - Linda H Malkas AU - Young Min Chung AU - Mickey C-T Hu AU - Yun Yen Y1 - 2015/03/26 UR - http://molpharm.aspetjournals.org/content/early/2015/03/26/mol.114.094987.abstract N2 - 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. ER -