title: 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) 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.
authors: Department of Radiobiology, Faculty of Military Health Sciences in Hradec Králové, University of Defence in Brno, Hradec Králové, Czech Republic.
authors: V
authors: V
authors: Mikusová
authors: A
authors: A
authors: Tichý
authors: M
authors: M
authors: Rezáčová
authors: J
authors: J
authors: Vávrová
mesh_terms: D017766:Acid Anhydride Hydrolases; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D018922:HL-60 Cells / Q000187:drug effects; D059765:Homologous Recombination; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000201:enzymology; D008942:Mitoxantrone / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; D008942:Mitoxantrone; D051747:DNA-Activated Protein Kinase; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes