title: 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: 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.
authors: Mei-Chuan
authors: MC
authors: Chen
authors: 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.
authors: Bingsen
authors: B
authors: Zhou
authors: 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.
authors: Keqiang
authors: K
authors: Zhang
authors: 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.
authors: Yate-Ching
authors: YC
authors: Yuan
authors: 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.
authors: Frank
authors: F
authors: Un
authors: 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.
authors: Shuya
authors: S
authors: Hu
authors: 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.
authors: Chih-Ming
authors: CM
authors: Chou
authors: 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.
authors: Chun-Han
authors: CH
authors: Chen
authors: 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.
authors: Jun
authors: J
authors: Wu
authors: 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.
authors: Yan
authors: Y
authors: Wang
authors: 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.
authors: Xiyong
authors: X
authors: Liu
authors: 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.
authors: D Lynne
authors: DL
authors: Smith
authors: 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.
authors: Hongzhi
authors: H
authors: Li
authors: 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.
authors: Zheng
authors: Z
authors: Liu
authors: 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.
authors: Charles D
authors: CD
authors: Warden
authors: 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.
authors: Leila
authors: L
authors: Su
authors: 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.
authors: Linda H
authors: LH
authors: Malkas
authors: 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.
authors: Young Min
authors: YM
authors: Chung
authors: 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.
authors: Mickey C-T
authors: MC
authors: Hu
authors: 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 yyen@tmu.edu.tw.
authors: Yun
authors: Y
authors: Yen
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D019313:BRCA1 Protein / Q000235:genetics; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D059766:DNA End-Joining Repair / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D005260:Female; D064593:Heterografts; D006801:Humans; D016688:Mice, Inbred NOD; D009152:Mutagenicity Tests; D009368:Neoplasm Transplantation; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D015027:Zebrafish
chemical_list: D000964:Antimetabolites, Antineoplastic; D019313:BRCA1 Protein; D001549:Benzamides; C000599194:N-(4-(3,4-dihydroxyphenyl)-5-phenylthiazol-2-yl)-3,4-dihydroxybenzamide; D013844:Thiazoles; D012264:Ribonucleotide Reductases