Radio-sensitization of human leukaemic molt-4 cells by DNA-dependent protein kinase inhibitor, NU7026
Language English Country Czech Republic Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Apoptosis radiation effects MeSH
- Cell Cycle radiation effects MeSH
- Chromones pharmacology MeSH
- Leukemia, T-Cell radiotherapy MeSH
- Humans MeSH
- Morpholines pharmacology MeSH
- Cell Line, Tumor radiation effects MeSH
- DNA Repair radiation effects MeSH
- DNA Damage radiation effects MeSH
- Cell Proliferation radiation effects MeSH
- DNA-Activated Protein Kinase antagonists & inhibitors MeSH
- Radiation-Sensitizing Agents pharmacology MeSH
- Radiation Tolerance drug effects MeSH
- Gamma Rays MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 2-(morpholin-4-yl)benzo(h)chromen-4-one MeSH Browser
- Chromones MeSH
- Morpholines MeSH
- DNA-Activated Protein Kinase MeSH
- Radiation-Sensitizing Agents MeSH
In this paper we describe the influence of NU7026, a specific inhibitor of DNA-dependent protein kinase, phosphoinositide 3-kinase, and ATM-kinase on molecular and cellular mechanisms triggered by ionising irradiation in human T-lymphocyte leukaemic MOLT-4 cells. We studied the effect of this inhibitor (10 1microM) combined with gamma-radiation (1 Gy) leading to DNA damage response and induction of apoptosis. We used methods for apoptosis assessment (cell viability count and flow-cytometric analysis) and cell cycle analysis (DNA content measurement) and we detected expression and post-translational modifications (Western blotting) of proteins involved in DNA repair signalling pathways. Pre-treatment with NU7026 resulted into decreased activation of checkpoint kinase-2 (Thr68), p53 (Ser15 and Ser392), and histone H2A.X (Ser139) 2 hours after irradiation. Subsequently, combination of radiation and inhibitor led to decreased amount of cells in G2-phase arrest and into increased apoptosis after 72 hours. Our results indicate that in leukaemic cells the pre-incubation with inhibitor NU7026 followed by low doses of ionising radiation results in radio-sensitising of MOLT-4 cells via diminished DNA repair and delayed but pronounced apoptosis. This novel approach might offer new strategies in combined treatment of leukaemia diseases.
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