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5285473 
Journal Article 
Inactivation of DNA-PK by knockdown DNA-PKcs or NU7441 impairs non-homologous end-joining of radiation-induced double strand break repair 
Dong, J; Ren, Y; Zhang, T; Wang, Z; Ling, CC; Li, GC; He, F; Wang, C; Wen, B 
2018 
1 
Oncology Reports
ISSN: 1021-335X
EISSN: 1791-2431 
39 
3 
912-920 
English 
29344644 
The DNA-dependent protein kinase (DNA-PK) complex plays a pivotal role in non-homologous end-joining (NHEJ) repair. We investigated the mechanism of NU7441, a highly selective DNA-PK inhibitor, in NHEJ-competent mouse embryonic fibroblast (MEF) cells and NHEJ-deficient cells and explored the feasibility of its application in radiosensitizing nasopharyngeal carcinoma (NPC) cells. We generated wild-type and DNA-PKcs-/- MEF cells. Clonogenic survival assays, flow cytometry, and immunoblotting were performed to study the effect of NU7441 on survival, cell cycle, and DNA repair. NU7441 profoundly radiosensitized wild-type MEF cells and SUNE-1 cells, but not DNA-PKcs-/- MEF cells. NU7441 significantly suppressed radiation-induced DSB repair post-irradiation through unrepaired and lethal DNA damage, the cell cycle arrest. The effect was associated with the activation of cell cycle checkpoints. The present study revealed a mechanism by which inhibition of DNA-PK sensitizes cells to irradiation suggesting that radiotherapy in combination with DNA-PK inhibitor is a promising paradigm for the management of NPC which merits further investigation.