Oncotarget

Research Papers:

DDRI-9: a novel DNA damage response inhibitor that blocks mitotic progression

Dong Wha Jun, Mihwa Hwang, Yun-Hee Kim, Kyung-Tae Kim, Sunshin Kim and Chang-Hun Lee _

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Oncotarget. 2016; 7:17699-17710. https://doi.org/10.18632/oncotarget.7135

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Abstract

Dong Wha Jun1,*, Mihwa Hwang1,5,*, Yun-Hee Kim3, Kyung-Tae Kim4, Sunshin Kim1 and Chang-Hun Lee2

1 New Experimental Therapeutics Branch, Division of Convergence Technology, National Cancer Center, Goyang, Gyeonggi, Korea

2 Cancer Cell and Molecular Biology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi, Korea

3 Molecular Imaging and Therapy Branch, Division of Convergence Technology, National Cancer Center, Goyang, Gyeonggi, Korea

4 Molecular Epidemiology Branch, Division of Cancer Epidemiology and Prevention, National Cancer Center, Goyang, Gyeonggi, Korea

5 System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, Korea

* These authors have contributed equally to this work

Correspondence to:

Sunshin Kim, email:

Chang-Hun Lee, email:

Keywords: DNA damage response, anticancer drugs, mitotic inhibitors, γH2AX, DNA repair-related proteins

Received: June 18, 2015 Accepted: January 19, 2016 Published: February 02, 2016

Abstract

The DNA damage response (DDR) is an emerging target for cancer therapy. By modulating the DDR, including DNA repair and cell cycle arrest, the efficacy of anticancer drugs can be enhanced and side effects reduced. We previously screened a chemical library and identified novel DDR inhibitors including DNA damage response inhibitor-9 (DDRI-9; 1H-Purine-2,6-dione,7-[(4-fluorophenyl)methyl]-3,7-dihydro-3-methyl-8-nitro). In this study, we characterized DDRI-9 activity and found that it inhibited phosphorylated histone variant H2AX foci formation upon DNA damage, delayed DNA repair, and enhanced the cytotoxicity of etoposide and ionizing radiation. It also reduced the foci formation of DNA repair-related proteins, including the protein kinase ataxia-telangiectasia mutated, DNA-dependent protein kinase, breast cancer type 1 susceptibility protein, and p53-binding protein 1, but excluding mediator of DNA damage checkpoint protein 1. Cell cycle analysis revealed that DDRI-9 blocked mitotic progression. Like other mitotic inhibitors, DDRI-9 treatment resulted in the accumulation of mitotic protein and induced cell death. Thus, DDRI-9 may affect both DDR signal amplification and mitotic progression. This study suggests that DDRI-9 is a good lead molecule for the development of anticancer drugs.


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