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Changes in the response of MCF-7 cells to ionizing radiation after the combination of ATM and DNA-PK inhibition
Authors: Cmielova Jana | Havelek Radim | Vavrova Jirina | Rezacova Martina
Year: 2015
Type of publication: článek v odborném periodiku
Name of source: Medical Oncology
Publisher name: Humana Press
Place: Totowa
Page from-to: "138-1"-"138-8"
Titles:
Language Name Abstract Keywords
cze Změny v odpovědi buněk MCF-7 na ionizující záření po kombinaci inhibice ATM a DNA-PK Tato práce popisuje roli inhibitorů ATM (KU55933) and DNA-PK (NU7441) v molekulární odpovědi buněk MCF-7 na účinky ionizujícího záření. ATM; DNA-PK; ionizující záření; H2AX; MCF-7
eng Changes in the response of MCF-7 cells to ionizing radiation after the combination of ATM and DNA-PK inhibition The aim of the present study is to evaluate the role of ATM (KU55933) and DNA-PK (NU7441) inhibitors in the repair of double-strand breaks and downstream signaling of DNA damage introduced by ionizing radiation. The irradiation of MCF-7 cells alone increased the proportion of cells in the G1 phase in comparison with mock-treated cells. After ATM inhibitor pretreatment, the cells were more accumulated in the G2 phase, whereas DNA-PK inhibitor application increased the percentage of cells in the G1 phase. ATM and DNA-PK inhibitor application alone increased the sensitivity of MCF-7 cells to ionizing radiation; however, combining both inhibitors together resulted in a further enhancement of cell death. Unexpectedly, combining both inhibitors decreased the percentage of senescent cells and increased G2 cell cycle arrest 3 days after treatment. After irradiation, the p21 protein was increased and Chk1 and Chk2 were activated. These proteins were not increased in cells pretreated with the ATM inhibitor prior to ionizing radiation exposure, albeit DNA-PK inhibitor application did not affect the amount of proteins detected. Formation of gamma H2AX was found to be ATM and DNA-PK dependent, application of the ATM inhibitor suppressed incidence of gamma H2AX, whereas DNA-PK caused persistence of gamma H2AX. Our results suggest that the further investigation of the ATM inhibitor in combination with the DNA-PK inhibitor as sensitizers preventing cell senescence and promoting cell death in breast carcinoma MCF-7 cells is warranted. ATM; DNA-PK; Ionizing radiation; H2AX; MCF-7

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