Radio-sensitization of human leukaemic MOLT-4 cells by DNA-dependent protein kinase inhibitor, NU7441
Jazyk angličtina Země Německo Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
- MeSH
- apoptóza účinky léků účinky záření MeSH
- časové faktory MeSH
- chromony farmakologie MeSH
- fosforylace účinky léků účinky záření MeSH
- histony metabolismus MeSH
- inhibitory proteinkinas farmakologie MeSH
- leukemie patologie MeSH
- lidé MeSH
- morfoliny farmakologie MeSH
- nádorové buněčné linie MeSH
- oprava DNA účinky léků účinky záření MeSH
- poškození DNA MeSH
- proliferace buněk účinky léků účinky záření MeSH
- proteinkinasa aktivovaná DNA antagonisté a inhibitory MeSH
- radiosenzibilizující látky farmakologie MeSH
- signální transdukce účinky léků účinky záření MeSH
- tolerance záření účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one MeSH Prohlížeč
- chromony MeSH
- H2AX protein, human MeSH Prohlížeč
- histony MeSH
- inhibitory proteinkinas MeSH
- morfoliny MeSH
- proteinkinasa aktivovaná DNA MeSH
- radiosenzibilizující látky 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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