title: The effect of ATM and ERK1/2 inhibition on mitoxantrone-induced cell death of leukaemic cells.
abstract: The relationship between signal pathways MEK1/2-ERK1/2 and ATM-p53 in the response to DNA damage is not well understood. The aim of our study was to investigate the effect of mitoxantrone and two protein kinase inhibitors - caffeine (inhibitor of ATM kinase) and U0126 (inhibitor of MEK1/2 kinase) - on MOLT-4 and Jurkat leukaemic cell lines. In this work we show that the inhibition of MEK1/2 is associated with an increased mortality of cells after mitoxantrone treatment. Inhibition of ATM by caffeine delayed mitoxantrone-induced cell death in MOLT-4 cells. Mitoxantrone itself induced cell-cycle arrest and accumulation of the cells in late S and G2/M phase. Inhibition of ATM, but not of MEK1/2, abrogated mitoxantrone-induced cell-cycle arrest. Inhibition of MEK1/2 did not change mitoxantroneinduced up-regulation of p53 and p21, but inhibition of ATM markedly decreased up-regulation of p53 and p21, and p53 phosphorylation on serine 15 and serine 392. It can be concluded that: 1) mitoxantrone- induced phosphorylation of p53 on serine 15 and serine 392 is ATM dependent and MEK1/2-ERK1/2 independent. 2) ATM inhibition by caffeine prevents G2 cell arrest and in p53-positive cells MOLT-4 delays the onset of mitoxantrone-induced cell death. 3) Inhibition of MEK1/2-ERK1/2 cascade potentiates the cytostatic effect of mitoxantrone regardless of the p53 status.
authors.affiliation: Charles University in Prague, Department of Medical Biochemistry, Hradec Králové, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Seifrtová
authors.forename: R
authors.initials: R
authors.lastname: Havelek
authors.forename: M
authors.initials: M
authors.lastname: Chmelařová
authors.forename: J
authors.initials: J
authors.lastname: Cmielová
authors.forename: D
authors.initials: D
authors.lastname: Muthná
authors.forename: A
authors.initials: A
authors.lastname: Stoklasová
authors.forename: S
authors.initials: S
authors.lastname: Zemánková
authors.forename: M
authors.initials: M
authors.lastname: Rezáčová
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D002070:Butadienes / Q000494:pharmacology; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics; D008942:Mitoxantrone / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D002070:Butadienes; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009570:Nitriles; D025521:Tumor Suppressor Proteins; C113580:U 0126; D008942:Mitoxantrone; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3