Mitoxantrone in Combination with a DNA-PK Inhibitor: Possible Therapy of Promyelocytic Leukaemia Resistant Forms
Abstract
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 - TI 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 TI II and reduced levels of TI II α and β.
The resistance of the HL-60/MX2 cells to MTX is associated with their increased ability to repair DSB. The HL-60/MX2 cells, compared to HL-60 cells (which are MTX-sensitive), contain large amounts of DNA-PK, which is responsible for the main pathway of the DSB repair, non-homogenous end joining (NHEJ), and they also contain large amounts of further repair proteins Rad50 and Nbs1, which are important in both NHEJ and homologous re-combination.
We demonstrated that specific DNA-PK inhibitor NU7026 in HL60/MX2 prevented DSB repair through the NHEJ pathway and essentially abolished the resistance to MTX.