title: Comparison of the Radiosensitizing Effect of ATR, ATM and DNA-PK Kinase Inhibitors on Cervical Carcinoma Cells.
abstract: Here, we compared the effects of inhibitors of three phosphatidylinositol-3-kinase-related kinases, ATM, ATR a DNA-PK, on radiosensitization of cervical carcinoma cells. We demonstrated that DNA-PK inhibitor NU7441 enhanced phosphorylation of Chk1 and Chk2 kinases 2 h after irradiation of HeLa cells at a dose of 8 Gy in contrast to ATM kinase inhibitor KU55933, which completely blocked the Chk2 kinase phosphorylation on threonine 68, and ATR kinase inhibitor VE-821, which blocked the Chk1 kinase phosphorylation on serine 345. Most HeLa cells were accumulated in G2 phase of the cell cycle 24 h after irradiation at a high dose of 15 Gy, which was even potentiated after adding the inhibitors NU7441 and KU55933. Compared to all other irradiated groups, inhibitor VE-821 increased the number of cells in S phase and reduced the number of cells in G2 phase 24 h after irradiation at the high dose of 15 Gy. HeLa cells entered the mitotic cycle with unrepaired DNA, which resulted in cell death and the radiosensitizing effect of VE-821. Short-term application of the inhibitors (2 h before and 30 min after the irradiation by the dose of 8 Gy) significantly decreased the colony-forming ability of HeLa cells. Using real-time monitoring of cell proliferation by the xCELLigence system we demonstrated that while the radiosensitizing effect of VE-821 (ATR inhibitor) is manifested early after the irradiation, the radiosensitizing effect of KU55933 (ATM inhibitor) and NU7441 (DNA-PK inhibitor) is only observed as late as 72 h after the irradiation.
authors.affiliation: Department of Radiobiology, Faculty of Military Health Sciences, Hradec Králové, University of Defence Brno, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Vávrová
authors.affiliation: Department of Radiobiology, Faculty of Military Health Sciences, Hradec Králové, University of Defence Brno, Czech Republic.
authors.forename: L
authors.initials: L
authors.lastname: Zárybnická
authors.affiliation: Centre of Advanced Studies, Faculty of Military Health Sciences, Hradec Králové, University of Defence Brno, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Jošt
authors.affiliation: Department of Radiobiology, Faculty of Military Health Sciences, Hradec Králové, University of Defence Brno, Czech Republic.
authors.forename: A
authors.initials: A
authors.lastname: Tichý
authors.affiliation: Institute of Medical Biochemistry, Charles University Prague, Faculty of Medicine in Hradec Králové, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Řezáčová
authors.affiliation: Department of Radiobiology, Faculty of Military Health Sciences, Hradec Králové, University of Defence Brno, Czech Republic.
authors.forename: Z
authors.initials: Z
authors.lastname: Šinkorová
authors.affiliation: Department of Radiobiology, Faculty of Military Health Sciences, Hradec Králové, University of Defence Brno, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Pejchal
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006367:HeLa Cells; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D002583:Uterine Cervical Neoplasms / Q000201:enzymology* / Q000473:pathology*
chemical_list: D047428:Protein Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase