2. Academic Validation
  3. The Novel Ribonucleotide Reductase Inhibitor COH29 Inhibits DNA Repair In Vitro

The Novel Ribonucleotide Reductase Inhibitor COH29 Inhibits DNA Repair In Vitro

  • Mol Pharmacol. 2015 Jun;87(6):996-1005. doi: 10.1124/mol.114.094987.
Mei-Chuan Chen 1,  Bingsen Zhou 1,  Keqiang Zhang 1,  Yate-Ching Yuan 1,  Frank Un 1,  Shuya Hu 1,  Chih-Ming Chou 1,  Chun-Han Chen 1,  Jun Wu 1,  Yan Wang 1,  Xiyong Liu 1,  D Lynne Smith 1,  Hongzhi Li 1,  Zheng Liu 1,  Charles D Warden 1,  Leila Su 1,  Linda H Malkas 1,  Young Min Chung 1,  Mickey C-T Hu 1,  Yun Yen 2
Affiliations

Affiliations

  • 1 Departments of Molecular Pharmacology (B.Z., K.Z., F.U., S.H., X.L., D.L.S., Y.Y.), Molecular Medicine (Y.-C.Y., H.L., Z.L., C.D.W., L.S.), Molecular and Cellular Biology (L.H.M.), and Division of Comparative Medicine (J.W., Y.W.), City of Hope National Medical Center, Duarte, California; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology Stanford University School of Medicine, Stanford, California; (Y.M.C., M.C.-T.H.); Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy (M.-C.C.), and Graduate Institute of Pharmacognosy, College of Pharmacy, (M.-C.C), Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology (C.-H.C., Y.Y.), and Department of Biochemistry, School of Medicine, College of Medicine (C.-M.C.), Taipei Medical University, Taipei, Taiwan.
  • 2 Departments of Molecular Pharmacology (B.Z., K.Z., F.U., S.H., X.L., D.L.S., Y.Y.), Molecular Medicine (Y.-C.Y., H.L., Z.L., C.D.W., L.S.), Molecular and Cellular Biology (L.H.M.), and Division of Comparative Medicine (J.W., Y.W.), City of Hope National Medical Center, Duarte, California; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology Stanford University School of Medicine, Stanford, California; (Y.M.C., M.C.-T.H.); Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy (M.-C.C.), and Graduate Institute of Pharmacognosy, College of Pharmacy, (M.-C.C), Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology (C.-H.C., Y.Y.), and Department of Biochemistry, School of Medicine, College of Medicine (C.-M.C.), Taipei Medical University, Taipei, Taiwan [email protected].
PMID: 25814515 DOI: 10.1124/mol.114.094987
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.

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