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

D. W. Jun, Y. S. Jeong, H. J. Kim, K. C. Jeong, S. Kim, C. H. Lee

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH 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. KEY 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 AND IMPLICATIONS 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.

Original languageEnglish
Pages (from-to)141-150
Number of pages10
JournalBritish Journal of Pharmacology
Volume167
Issue number1
DOIs
StatePublished - Sep 2012

Keywords

  • γH2AX
  • anticancer agents
  • DNA damage response
  • small molecule

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