Fol. Biol. 2011, 57, 200-205

https://doi.org/10.14712/fb2011057050200

Mitoxantrone in Combination with a DNA-PK Inhibitor: Possible Therapy of Promyelocytic Leukaemia Resistant Forms

V. Mikusová1, A. Tichý1, M. Řezáčová2, Jiřina Vávrová1

1Department of Radiobiology, Faculty of Military Health Sciences in Hradec Králové, University of Defence in Brno, Hradec Králové, Czech Republic
2Department of Medical Biochemistry, Faculty of Medicine in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic

Received March 2011
Accepted May 2011

The aim of the study was to sensitize cells of human promyelocytic leukaemia HL-60/MX2 (resistant to mitoxantrone and further substances interacting with topoisomerase II) to the effect of mitoxantrone (MTX). We demonstrated that the main mechanism of the HL-60/MX2 cell atypical multiple drug resistance is not only their altered activity of topoisomerase II and reduced levels of topoisomerase II α and β proteins. The resistance of the HL-60/ MX2 cells to MTX is associated with their increased ability to repair DNA double-strand breaks (DSBs) in these cells. The HL-60/MX2 cells, compared to HL-60 cells (which are sensitive to MTX effects), contain large amounts of DNA-PK, which is responsible for the main pathway of the DSB repair, nonhomogenous end joining (NHEJ), and they also contain large amounts of further repair proteins Rad50 and Nbs1, which are important in both types of the repair processes (NHEJ as well as homologous recombination). We demonstrated that specific DNAPK inhibitor NU7026 reduced the amount of DNAPK in HL60/MX2, thus preventing the DSB repair through the NHEJ pathway after the incubation with MTX and in this way essentially abolished the resistance of these cells to MTX.

Funding

This study was financially supported by the Ministry of Defence of the Czech Republic – project MO0FVZ0000501.

References

16 live references