title: Characterization of DDRI-18 (3,3'-(1H,3'H-5,5'-bibenzo[d]imidazole-2,2'-diyl)dianiline), a novel small molecule inhibitor modulating the DNA damage response.
abstract: OBJECTIVE
  Recently, the DNA damage response (DDR) has emerged as a promising target for anticancer drug development. In our previous study, we identified several DDR-inhibiting compounds via high-content screening of a small molecule library using γH2AX foci as a biomarker. Here, we studied the effects of the DNA damage response inhibitor DDRI-18 (3,3'-(1H,3'H-5,5'-bibenzo[d]imidazole-2,2'-diyl)dianiline) on DDR.
  
  
  METHODS
  Osteosarcoma U2OS cells were treated with etoposide to induce DDR. The nuclear foci of γH2AX and other signalling molecules in DDR were visualized by immunofluorescence and quantified using an IN Cell Analyzer. The DNA repair capacity of cells was analysed using the comet assay and in vivo DNA end-joining assay. Cell survival after drug treatment was quantified using the MTT assay, and apoptotic cell death was analysed by Annexin V staining and flow cytometry.
  
  
  RESULTS
  DDRI-18 inhibited the non-homologous end-joining (NHEJ) DNA repair process and delayed the resolution of DNA damage-related proteins (γH2AX, ATM and BRCA1) from DNA lesions at a later phase of DDR. Furthermore, DDRI-18 enhanced the cytotoxic effects of anticancer DNA-damaging drugs, including etoposide, camptothecin, doxorubicin and bleomycin. This synergistic effect on cell death was shown to be due to caspase-dependent apoptosis.
  
  
  CONCLUSIONS
  We identified a chemical compound, DDRI-18, that has chemosensitization activity. Although the target molecule and mechanism of action of DDRI-18 remain unknown, DDRI-18 is an effective chemosensitizing agent and may improve the therapy with classical anticancer drugs.
authors.affiliation: Carcinogenesis Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi, Korea.
authors.forename: D W
authors.initials: DW
authors.lastname: Jun
authors.forename: Y S
authors.initials: YS
authors.lastname: Jeong
authors.forename: H J
authors.initials: HJ
authors.lastname: Kim
authors.forename: K-C
authors.initials: KC
authors.lastname: Jeong
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: C-H
authors.initials: CH
authors.lastname: Lee
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D006801:Humans
chemical_list: C577084:3,3'-(1H,3'H-5,5'-bibenzo(d)imidazole-2,2'-diyl)dianiline; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D001761:Bleomycin; D005047:Etoposide; D002166:Camptothecin