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DNA repair inhibitors as radiosensitizers in human lung cells
Kamila Ďurišová, Lucie Čecháková, Petr Jošt, Zuzana Šinkorová, Adéla Kmochová, Jaroslav Pejchal, Martin Ondrej, Jiřina Vávrová, Aleš Tichý
Jazyk angličtina Země Česko
Typ dokumentu práce podpořená grantem
- MeSH
- enzymy opravy DNA antagonisté a inhibitory genetika MeSH
- fibroblasty účinky záření MeSH
- kultivované buňky účinky záření MeSH
- nádorové buňky kultivované účinky léků účinky záření MeSH
- nemalobuněčný karcinom plic genetika radioterapie MeSH
- oprava DNA účinky léků MeSH
- proliferace buněk účinky záření MeSH
- radiosenzibilizující látky farmakologie izolace a purifikace terapeutické užití MeSH
- techniky in vitro MeSH
- Publikační typ
- práce podpořená grantem MeSH
The aim of this study was to compare the effects of DNA repair inhibitors in the context of radio-sensitization of human lung cells. The radio-sensitizing effects of NU7441 (1 mM), an inhibitor of DNA-dependent protein kinase (DNA-PK); KU55933 (10 μM), an inhibitor of ataxia-telangiectasia mutated kinase (ATM); and VE-821 (10 μM), an inhibitor of ATM-related kinase (ATR) were tested by the xCELLigence system for monitoring proliferation, fluorescence microscopy for DNA damage detection, flow-cytometry for cell cycle and apoptosis analysis and western blotting and ELISA for determination of DNA repair proteins. We employed normal human lung fibroblasts (NHLF, p53-wild-type) and non-small cell lung cancer cells (H1299, p53-negative). DNA-PK inhibition (by NU7441) in combination with ionizing radiation (IR) increased the number of double strand breaks (DSB), which persisted 72 h after irradiation in both cell lines. Additionally, NU7441 and KU55933 in combination with IR caused G2-arrest. ATR inhibitor (VE-821) together with IR markedly inhibited proliferation and induced G2/M arrest accompanied by apoptosis in H1299, but not in NHLF cells, and thus diminished DNA-repair of tumour cells but not normal lung fibroblasts. Our findings indicate that ATR inhibition could be a promising therapeutic strategy in p53-deficient lung tumours.
Citace poskytuje Crossref.org
Literatura
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- $a The aim of this study was to compare the effects of DNA repair inhibitors in the context of radio-sensitization of human lung cells. The radio-sensitizing effects of NU7441 (1 mM), an inhibitor of DNA-dependent protein kinase (DNA-PK); KU55933 (10 μM), an inhibitor of ataxia-telangiectasia mutated kinase (ATM); and VE-821 (10 μM), an inhibitor of ATM-related kinase (ATR) were tested by the xCELLigence system for monitoring proliferation, fluorescence microscopy for DNA damage detection, flow-cytometry for cell cycle and apoptosis analysis and western blotting and ELISA for determination of DNA repair proteins. We employed normal human lung fibroblasts (NHLF, p53-wild-type) and non-small cell lung cancer cells (H1299, p53-negative). DNA-PK inhibition (by NU7441) in combination with ionizing radiation (IR) increased the number of double strand breaks (DSB), which persisted 72 h after irradiation in both cell lines. Additionally, NU7441 and KU55933 in combination with IR caused G2-arrest. ATR inhibitor (VE-821) together with IR markedly inhibited proliferation and induced G2/M arrest accompanied by apoptosis in H1299, but not in NHLF cells, and thus diminished DNA-repair of tumour cells but not normal lung fibroblasts. Our findings indicate that ATR inhibition could be a promising therapeutic strategy in p53-deficient lung tumours.
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