VX-984 is a selective inhibitor of non-homologous end joining, with possible preferential activity in transformed cells.

Autor:	Khan AJ; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10011, USA.; Department of Radiation Oncology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA., Misenko SM; Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA., Thandoni A; Department of Radiation Oncology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA., Schiff D; Department of Radiation Oncology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA., Jhawar SR; Department of Radiation Oncology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA., Bunting SF; Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA., Haffty BG; Department of Radiation Oncology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2018 May 25; Vol. 9 (40), pp. 25833-25841. Date of Electronic Publication: 2018 May 25 (Print Publication: 2018).
DOI:	10.18632/oncotarget.25383
Abstrakt:	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 EJ-DR) 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. Competing Interests: CONFLICTS OF INTEREST The authors report no conflicts of interest.
Databáze:	MEDLINE
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