We evaluated the impact of ataxia-telangiectasia mutated kinase inhibitor KU55933, DNA-dependent protein kinase inhibitor NU7441 and ataxia telangiectasia and rad3-related kinase inhibitor VE821 in human peripheral lymphocytes in vitro. The lymphocytes were divided into 5 groups: non-irradiated control, irradiated group (2 Gy) and 3 groups pretreated with inhibitors 30 min before irradiation. We used flow cytometry to evaluate phosphorylated H2AX (γ-H2AX) and cytotoxicity (Apoptest). Micronucleus assay was used to assess genotoxicity. After irradiation, γ-H2AX, incidence of micronuclei (MN), nucleoplasmatic bridges (NPBs) and nuclear buds in binuclear cells, MN in mononuclear cells and apoptosis were increased. KU55933 decreased γ-H2AX and inhibited ionizing radiation-induced cytotoxicity. NU7441 showed no effect on γ-H2AX but it significantly increased MN and NPBs in binuclear cells and apoptosis. VE821 decreased γ-H2AX, whereas genotoxicity and cytotoxicity were not affected. In conclusion, KU55933 protected lymphocytes, which might be employed to preserve the immune system during anticancer therapy. NU7441 radiosensitized lymphocytes, thus, undesirable side effects toward immune system could be expected. VE821 showed decrease of γ-H2AX with no radiosensitizing effects in our model likely due to p53 positive status, which underlies the concept of its application in p53 negative environment.

Biomedicine Research Center Faculty Hospital Sokolska 581 500 05 Hradec Kralove Czech Republic

c Department of Blood Transfusion Faculty Hospital Sokolska 581 500 05 Hradec Kralove Czech Republic

Department of Molecular Biology and Pathology Faculty of Military Health Sciences University of Defence Trebesska 1575 500 01 Hradec Kralove Czech Republic

Department of Radiobiology Faculty of Military Health Sciences in Hradec Kralove University of Defence Trebesska 1575 500 01 Hradec Kralove Czech Republic

Literatura

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$a Kmochová, Adéla $7 xx0225217 $u Department of Radiobiology, Faculty of Military Health Sciences in Hradec Kralove, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic

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$a Modulation of ionizing radiation-induced effects by NU7441, KU55933 and VE821 in peripheral blood lymphocytes / $c Adela Kmochova, Ales Tichy, Lenka Zarybnicka, Zuzana Sinkorova, Jirina Vavrova, Vit Rehacek, Kamila Durisova, Klara Kubelkova, Jaroslav Pejchal, Kamil Kuca

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$a We evaluated the impact of ataxia-telangiectasia mutated kinase inhibitor KU55933, DNA-dependent protein kinase inhibitor NU7441 and ataxia telangiectasia and rad3-related kinase inhibitor VE821 in human peripheral lymphocytes in vitro. The lymphocytes were divided into 5 groups: non-irradiated control, irradiated group (2 Gy) and 3 groups pretreated with inhibitors 30 min before irradiation. We used flow cytometry to evaluate phosphorylated H2AX (γ-H2AX) and cytotoxicity (Apoptest). Micronucleus assay was used to assess genotoxicity. After irradiation, γ-H2AX, incidence of micronuclei (MN), nucleoplasmatic bridges (NPBs) and nuclear buds in binuclear cells, MN in mononuclear cells and apoptosis were increased. KU55933 decreased γ-H2AX and inhibited ionizing radiation-induced cytotoxicity. NU7441 showed no effect on γ-H2AX but it significantly increased MN and NPBs in binuclear cells and apoptosis. VE821 decreased γ-H2AX, whereas genotoxicity and cytotoxicity were not affected. In conclusion, KU55933 protected lymphocytes, which might be employed to preserve the immune system during anticancer therapy. NU7441 radiosensitized lymphocytes, thus, undesirable side effects toward immune system could be expected. VE821 showed decrease of γ-H2AX with no radiosensitizing effects in our model likely due to p53 positive status, which underlies the concept of its application in p53 negative environment.

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$a Účinky ionizujícího záření způsobené inhibitory ATM (KU55933), DNA-PK (NU7441) a ATR (VE821) na lymfocyty periferní krve

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$a Tichý, Aleš, $d 1980- $7 xx0135624 $u Department of Radiobiology, Faculty of Military Health Sciences in Hradec Kralove, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic

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$a Šinkorová, Zuzana, $d 1963- $7 xx0106471 $u Department of Radiobiology, Faculty of Military Health Sciences in Hradec Kralove, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic

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$a Kubelková, Klára $7 hka2017949672 $u Department of Molecular Biology and Pathology, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic

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$a Pejchal, Jaroslav $7 xx0102560 $u Department of Radiobiology, Faculty of Military Health Sciences in Hradec Kralove, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic

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$a Kuča, Kamil, $d 1978- $7 xx0041831 $u Biomedicine Research Center, Faculty Hospital, Sokolska 581, 500 05 Hradec Kralove, Czech Republic

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