title: Repairing of N-mustard derivative BO-1055 induced DNA damage requires NER, HR, and MGMT-dependent DNA repair mechanisms.
abstract: Alkylating agents are frequently used as first-line chemotherapeutics for various newly diagnosed cancers. Disruption of genome integrity by such agents can lead to cell lethality if DNA lesions are not removed. Several DNA repair mechanisms participate in the recovery of mono- or bi-functional DNA alkylation. Thus, DNA repair capacity is correlated with the therapeutic response. Here, we assessed the function of novel water-soluble N-mustard BO-1055 (ureidomustin) in DNA damage response and repair mechanisms. As expected, BO-1055 induces ATM and ATR-mediated DNA damage response cascades, including downstream Chk1/Chk2 phosphorylation, S/G2 cell-cycle arrest, and cell death. Further investigation revealed that cell survival sensitivity to BO-1055 is comparable to that of mitomycin C. Both compounds require nucleotide excision repair and homologous recombination, but not non-homologous end-joining, to repair conventional cross-linking DNA damage. Interestingly and unlike mitomycin C and melphalan, MGMT activity was also observed in BO-1055 damage repair systems, which reflects the occurrence of O-alkyl DNA lesions. Combined treatment with ATM/ATR kinase inhibitors significantly increases BO-1055 sensitivity. Our study pinpoints that BO-1055 can be used for treating tumors that with deficient NER, HR, and MGMT DNA repair genes, or for synergistic therapy in tumors that DNA damage response have been suppressed.
authors.affiliation: Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
authors.forename: Ching-Ying
authors.initials: CY
authors.lastname: Kuo
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Chou
authors.affiliation: Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
authors.forename: Chin-Chung
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
authors.forename: Teng-Song
authors.initials: TS
authors.lastname: Wong
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kakadiya
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Te-Chang
authors.initials: TC
authors.lastname: Lee
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Tsann-Long
authors.initials: TL
authors.lastname: Su
authors.affiliation: Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.|PhD Program in Translational Medicine, College of Medicine/PhD Program in Toxicology, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.|Translational Research Center and Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan.|Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.
authors.forename: Hui-Chun
authors.initials: HC
authors.lastname: Wang
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016466:CHO Cells; D016923:Cell Death / Q000187:drug effects; D003412:Cricetulus; D004249:DNA Damage; D015254:DNA Modification Methylases / Q000378:metabolism*; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D008558:Melphalan / Q000494:pharmacology; D016685:Mitomycin / Q000494:pharmacology; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D059767:Recombinational DNA Repair; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C582286:1-(3-((2-(dimethylamino)ethyl)carbamoyl)phenyl)-3-(4-(bis(2-chloroethyl)amino)phenyl)urea; D018906:Antineoplastic Agents, Alkylating; D009588:Nitrogen Mustard Compounds; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D025521:Tumor Suppressor Proteins; D016685:Mitomycin; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D045643:DNA Repair Enzymes; D008558:Melphalan
keywords: DNA repair; DSBR; NER; alkylation agents; checkpoint