Radio-sensitization of human leukaemic MOLT-4 cells by DNA-dependent protein kinase inhibitor, NU7441
Language English Country Germany Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Apoptosis drug effects radiation effects MeSH
- Time Factors MeSH
- Chromones pharmacology MeSH
- Phosphorylation drug effects radiation effects MeSH
- Histones metabolism MeSH
- Protein Kinase Inhibitors pharmacology MeSH
- Leukemia pathology MeSH
- Humans MeSH
- Morpholines pharmacology MeSH
- Cell Line, Tumor MeSH
- DNA Repair drug effects radiation effects MeSH
- DNA Damage MeSH
- Cell Proliferation drug effects radiation effects MeSH
- DNA-Activated Protein Kinase antagonists & inhibitors MeSH
- Radiation-Sensitizing Agents pharmacology MeSH
- Signal Transduction drug effects radiation effects MeSH
- Radiation Tolerance drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one MeSH Browser
- Chromones MeSH
- H2AX protein, human MeSH Browser
- Histones MeSH
- Protein Kinase Inhibitors MeSH
- Morpholines MeSH
- DNA-Activated Protein Kinase MeSH
- Radiation-Sensitizing Agents MeSH
We studied the effect of pre-incubation with NU7441, a specific inhibitor of DNA-dependent protein kinase (DNA-PK), on molecular mechanisms triggered by ionizing radiation (IR). The experimental design involved four groups of human T-lymphocyte leukaemic MOLT-4 cells: control, NU7441-treated (1 μM), IR-treated (1 Gy), and combination of NU7441 and IR. We used flow cytometry for apoptosis assessment, Western blotting and ELISA for detection of proteins involved in DNA repair signalling and epifluorescence microscopy for detection of IR-induced phosphorylation of histone H2A.X. We did not observe any major changes in the amount of DNA-PK subunits Ku70/80 caused by the combination of NU7441 and radiation. Their combination led to an increased phosphorylation of H2A.X, a hallmark of DNA damage. However, it did not prevent up-regulation of neither p53 (and its phosphorylation at Ser 15 and 392) nor p21. We observed a decrease in the levels of anti-apoptotic Mcl-1, cdc25A phosphatase, cleavage of PARP and a significant increase in apoptosis in the group treated with combination. In conclusion, the combination of NU7441 with IR caused increased phosphorylation of H2A.X early after irradiation and subsequent induction of apoptosis. It was efficient in MOLT-4 cells in 10× lower concentration than the inhibitor NU7026. NU7441 proved as a potent radio-sensitizing agent, and it might provide a platform for development of new radio-sensitizers in radiotherapy.
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