VX-984 is a selective inhibitor of non-homologous end joining, with possible preferential activity in transformed cells Journal Article
| Authors: | Khan, A. J.; Misenko, S. M.; Thandoni, A.; Schiff, D.; Jhawar, S. R.; Bunting, S. F.; Haffty, B. G. |
| Article Title: | VX-984 is a selective inhibitor of non-homologous end joining, with possible preferential activity in transformed cells |
| Abstract: | Purpose: DNA double-strand breaks (DSBs) can be repaired by non-homologous end joining (NHEJ) or homologous recombination (HR). We demonstrate the selectivity of VX-984, a DNA-PK inhibitor, using assays not previously reported. Experimental Design: The class switch recombination assay (CSR) in primary B cells was used to measure efficiency of NHEJ. A cellular reporter assay (U2OS EJDR) was used to assess the efficiency of HR and NHEJ in cells treated with VX-984. Immunofluorescence assays (IF) evaluated γ-H2AX foci for DSB repair kinetics in human astrocytes and T98G glioma cells. Western blotting was used to evaluate phosphorylation of DNA-PKcs substrates. Results: We found a dose-dependent reduction in CSR efficiency with VX- 984, and through the EJ-DR assay, dramatic dose-dependent increases in HR and mNHEJ. Immunofluorescence assays showed an inability of malignant cells to resolve γ-H2AX foci in the presence of VX-984. Radiation-induced phosphorylation of DNA-PK substrates was further reduced by treatment with VX-984. Conclusions: VX-984 efficiently inhibits NHEJ, resulting in compensatory increases in alternative repair pathways, increases DSBs, and appears to affect transformed cells preferentially. © Khan et al. |
| Keywords: | controlled study; unclassified drug; human cell; homologous recombination; dna repair; radiation; protein kinase inhibitor; astrocyte; drug potency; immunofluorescence; enzyme substrate; phosphorylation; b lymphocyte; cell transformation; cancer cell; bioassay; western blotting; radiation therapy; histone h2ax; concentration response; double-strand break repair; non-homologous end joining; dna dependent protein kinase; dna-pk; dna end joining repair; human; article; vx 984; class switch recombination assay; ej-dr assay; t98g cell line; u2os cell line |
| Journal Title: | Oncotarget |
| Volume: | 9 |
| Issue: | 40 |
| ISSN: | 1949-2553 |
| Publisher: | Impact Journals |
| Date Published: | 2018-05-25 |
| Start Page: | 25833 |
| End Page: | 25841 |
| Language: | English |
| DOI: | 10.18632/oncotarget.25383 |
| PROVIDER: | scopus |
| PMCID: | PMC5995231 |
| PUBMED: | 29899825 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 July 2018 -- Source: Scopus |
