title: Cell-cycle changes and oxidative stress response to magnetite in A549 human lung cells.
abstract: In a recent study, magnetite was investigated for its potential to induce toxic effects and influence signaling pathways. It was clearly demonstrated that ROS formation leads to mitochondrial damage and genotoxic effects in A549 cells. On the basis of these findings, we wanted to elucidate the origin of magnetite-mediated ROS formation and its influence on the cell cycle of A549 and H1299 human lung epithelial cells. Concentration- and size-dependent superoxide formation, measured by electron paramagnetic resonance (EPR), was observed. Furthermore, we could show that the GSH level decreased significantly after exposure to magnetite particles, while catalase (CAT) activity was increased. These effects were also dependent on particle size, albeit less pronounced than those observed with EPR. We were able to show that incubation of A549 cells prior to particle treatment with diphenyleneiodonium (DPI), a NADPH-oxidase (NOX) inhibitor, leads to decreased ROS formation, but this effect was not observed for the NOX inhibitor apocynin. Soluble iron does not contribute considerably to ROS production. Analysis of cell-cycle distribution revealed a pronounced sub-G1 peak, which cannot be linked to increased cell death. Western blot analysis did not show activation of p53 but upregulation of p21 in A549. Here, we were unexpectedly able to demonstrate that exposure to magnetite leads to p21-mediated G1-like arrest. This has been reported previously only for low concentrations of microtubule stabilization drugs. Importantly, the arrested sub-G1 cells were viable and showed no caspase 3/7 activation.
authors.affiliation: Department of Environmental Health Sciences, University Medical Center Freiburg , Freiburg, Germany. mathias.koenczoel@pharmazie.uni-freiburg.de
authors.forename: Mathias
authors.initials: M
authors.lastname: Könczöl
authors.forename: Adilka
authors.initials: A
authors.lastname: Weiss
authors.forename: Evi
authors.initials: E
authors.lastname: Stangenberg
authors.forename: Richard
authors.initials: R
authors.lastname: Gminski
authors.forename: Manuel
authors.initials: M
authors.lastname: Garcia-Käufer
authors.forename: Reto
authors.initials: R
authors.lastname: Gieré
authors.forename: Irmgard
authors.initials: I
authors.lastname: Merfort
authors.forename: Volker
authors.initials: V
authors.lastname: Mersch-Sundermann
mesh_terms: D002453:Cell Cycle / Q000187:drug effects*; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D008168:Lung / Q000473:pathology*; D058185:Magnetite Nanoparticles / Q000737:chemistry*; D009861:Onium Compounds / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D054462:p21-Activated Kinases / Q000378:metabolism
chemical_list: D058185:Magnetite Nanoparticles; D009861:Onium Compounds; D017382:Reactive Oxygen Species; C007517:diphenyleneiodonium; D054462:p21-Activated Kinases