RRC ID 64540
Author Sunada S, Kanai H, Lee Y, Yasuda T, Hirakawa H, Liu C, Fujimori A, Uesaka M, Okayasu R.
Title Nontoxic concentration of DNA-PK inhibitor NU7441 radio-sensitizes lung tumor cells with little effect on double strand break repair.
Journal Cancer Sci
Abstract High-linear energy transfer (LET) heavy ions have been increasingly employed as a useful alternative to conventional photon radiotherapy. As recent studies suggested that high LET radiation mainly affects the nonhomologous end-joining (NHEJ) pathway of DNA double strand break (DSB) repair, we further investigated this concept by evaluating the combined effect of an NHEJ inhibitor (NU7441) at a non-toxic concentration and carbon ions. NU7441-treated non-small cell lung cancer (NSCLC) A549 and H1299 cells were irradiated with X-rays and carbon ions (290 MeV/n, 50 keV/μm). Cell survival was measured by clonogenic assay. DNA DSB repair, cell cycle distribution, DNA fragmentation and cellular senescence induction were studied using a flow cytometer. Senescence-associated protein p21 was detected by western blotting. In the present study, 0.3 μM of NU7441, nontoxic to both normal and tumor cells, caused a significant radio-sensitization in tumor cells exposed to X-rays and carbon ions. This concentration did not seem to cause inhibition of DNA DSB repair but induced a significant G2/M arrest, which was particularly emphasized in p53-null H1299 cells treated with NU7441 and carbon ions. In addition, the combined treatment induced more DNA fragmentation and a higher degree of senescence in H1299 cells than in A549 cells, indicating that DNA-PK inhibitor contributes to various modes of cell death in a p53-dependent manner. In summary, NSCLC cells irradiated with carbon ions were radio-sensitized by a low concentration of DNA-PK inhibitor NU7441 through a strong G2/M cell cycle arrest. Our findings may contribute to further effective radiotherapy using heavy ions.
Volume 107(9)
Pages 1250-5
Published 2016-9-1
DOI 10.1111/cas.12998
PMID 27341700
PMC PMC5021029
MeSH Cell Line, Tumor Cell Survival / drug effects Cell Survival / radiation effects Chromones / pharmacology* DNA Breaks, Double-Stranded* DNA Repair / drug effects* DNA Repair / radiation effects DNA-Activated Protein Kinase / antagonists & inhibitors* G2 Phase Cell Cycle Checkpoints / drug effects G2 Phase Cell Cycle Checkpoints / radiation effects Humans Linear Energy Transfer Lung Neoplasms Morpholines / pharmacology* Radiation-Sensitizing Agents / pharmacology*
Human and Animal Cells A549