The Novel Ribonucleotide Reductase Inhibitor COH29 Inhibits DNA Repair In Vitro.

Abstract

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.

• Authors: Mei-Chuan Chen, Bingsen Zhou, Keqiang Zhang, Yate-Ching Yuan, Frank Un, Shuya Hu, Chih-Ming Chou, Chun-Han Chen, Jun Wu, Yan Wang, Xiyong Liu, D Lynne Smith, Hongzhi Li, Zheng Liu, Charles D Warden, Leila Su, Linda H Malkas, Young Min Chung, Mickey C-T Hu, Yun Yen
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 87 Issue 6 Pg. 996-1005 (Jun 2015) ISSN: 1521-0111 [Electronic] United States
• PMID: 25814515 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Antimetabolites, Antineoplastic
• BRCA1 Protein
• Benzamides
• N-(4-(3,4-dihydroxyphenyl)-5-phenylthiazol-2-yl)-3,4-dihydroxybenzamide
• Thiazoles
• Ribonucleotide Reductases

Topics

• Animals
• Antimetabolites, Antineoplastic (pharmacology, therapeutic use)
• BRCA1 Protein (genetics)
• Benzamides (pharmacology, therapeutic use)
• Breast Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• DNA Breaks, Double-Stranded (drug effects)
• DNA End-Joining Repair (drug effects)
• DNA Repair (drug effects)
• Female
• Heterografts
• Humans
• Mice, Inbred NOD
• Mutagenicity Tests
• Neoplasm Transplantation
• Ribonucleotide Reductases (antagonists & inhibitors)
• Thiazoles (pharmacology, therapeutic use)
• Zebrafish