title: Localized Irradiation of Cell Membrane by Auger Electrons Is Cytotoxic Through Oxidative Stress-Mediated Nontargeted Effects.
abstract: We investigated whether radiation-induced nontargeted effects are involved in the cytotoxic effects of anticell surface monoclonal antibodies labeled with Auger electron emitters, such as iodine 125 (monoclonal antibodies labeled with (125)I [(125)I-mAbs]).
  
  
  
  We showed that the cytotoxicity of (125)I-mAbs targeting the cell membrane of p53(+/+) HCT116 colon cancer cells is mainly due to nontargeted effects. Targeted and nontargeted cytotoxicities were inhibited in vitro following lipid raft disruption with Methyl-β-cyclodextrin (MBCD) or filipin or use of radical oxygen species scavengers. (125)I-mAb efficacy was associated with acid sphingomyelinase activation and modulated through activation of the AKT, extracellular signal-related kinase ½ (ERK1/2), p38 kinase, c-Jun N-terminal kinase (JNK) signaling pathways, and also of phospholipase C-γ (PLC-γ), proline-rich tyrosine kinase 2 (PYK-2), and paxillin, involved in Ca(2+) fluxes. Moreover, the nontargeted response induced by directing 5-[(125)I]iodo-2'-deoxyuridine to the nucleus was comparable to that of (125)I-mAb against cell surface receptors. In vivo, we found that the statistical significance of tumor growth delay induced by (125)I-mAb was removed after MBCD treatment and observed oxidative DNA damage beyond the expected Auger electron range. These results suggest the involvement of nontargeted effects in vivo also.
  
  
  
  Low-energy Auger electrons, such as those emitted by (125)I, have a short tissue range and are usually targeted to the nucleus to maximize their cytotoxicity. In this study, we show that targeting the cancer cell surface with (125)I-mAbs produces a lipid raft-mediated nontargeted response that compensates for the inferior efficacy of non-nuclear targeting.
  
  
  
  Our findings describe the mechanisms involved in the efficacy of (125)I-mAbs targeting the cancer cell surface. Antioxid. Redox Signal. 25, 467-484.
authors.affiliation: 1 Institut de Recherche en Cancérologie de Montpellier (IRCM) , Montpellier, France .|2 INSERM , U1194, Montpellier, France .|3 Université de Montpellier , Montpellier, France .|4 Institut régional du Cancer de Montpellier , Montpellier, France .|5 Barts Cancer Institute, Queen Mary University of London , London, United Kingdom .
authors.forename: Salomé
authors.initials: S
authors.lastname: Paillas
authors.affiliation: 1 Institut de Recherche en Cancérologie de Montpellier (IRCM) , Montpellier, France .|2 INSERM , U1194, Montpellier, France .|3 Université de Montpellier , Montpellier, France .|4 Institut régional du Cancer de Montpellier , Montpellier, France .
authors.forename: Riad
authors.initials: R
authors.lastname: Ladjohounlou
authors.affiliation: 1 Institut de Recherche en Cancérologie de Montpellier (IRCM) , Montpellier, France .|2 INSERM , U1194, Montpellier, France .|3 Université de Montpellier , Montpellier, France .|4 Institut régional du Cancer de Montpellier , Montpellier, France .
authors.forename: Catherine
authors.initials: C
authors.lastname: Lozza
authors.affiliation: 1 Institut de Recherche en Cancérologie de Montpellier (IRCM) , Montpellier, France .|2 INSERM , U1194, Montpellier, France .|3 Université de Montpellier , Montpellier, France .|4 Institut régional du Cancer de Montpellier , Montpellier, France .
authors.forename: Alexandre
authors.initials: A
authors.lastname: Pichard
authors.affiliation: 1 Institut de Recherche en Cancérologie de Montpellier (IRCM) , Montpellier, France .|2 INSERM , U1194, Montpellier, France .|3 Université de Montpellier , Montpellier, France .|4 Institut régional du Cancer de Montpellier , Montpellier, France .
authors.forename: Vincent
authors.initials: V
authors.lastname: Boudousq
authors.affiliation: 4 Institut régional du Cancer de Montpellier , Montpellier, France .
authors.forename: Marta
authors.initials: M
authors.lastname: Jarlier
authors.affiliation: 1 Institut de Recherche en Cancérologie de Montpellier (IRCM) , Montpellier, France .|2 INSERM , U1194, Montpellier, France .|3 Université de Montpellier , Montpellier, France .|4 Institut régional du Cancer de Montpellier , Montpellier, France .
authors.forename: Samuel
authors.initials: S
authors.lastname: Sevestre
authors.affiliation: 1 Institut de Recherche en Cancérologie de Montpellier (IRCM) , Montpellier, France .|2 INSERM , U1194, Montpellier, France .|3 Université de Montpellier , Montpellier, France .|4 Institut régional du Cancer de Montpellier , Montpellier, France .
authors.forename: Marion
authors.initials: M
authors.lastname: Le Blay
authors.affiliation: 1 Institut de Recherche en Cancérologie de Montpellier (IRCM) , Montpellier, France .|2 INSERM , U1194, Montpellier, France .|3 Université de Montpellier , Montpellier, France .|4 Institut régional du Cancer de Montpellier , Montpellier, France .
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Deshayes
authors.affiliation: 5 Barts Cancer Institute, Queen Mary University of London , London, United Kingdom .
authors.forename: Jane
authors.initials: J
authors.lastname: Sosabowski
authors.affiliation: 1 Institut de Recherche en Cancérologie de Montpellier (IRCM) , Montpellier, France .|2 INSERM , U1194, Montpellier, France .|3 Université de Montpellier , Montpellier, France .|4 Institut régional du Cancer de Montpellier , Montpellier, France .
authors.forename: Thierry
authors.initials: T
authors.lastname: Chardès
authors.affiliation: 1 Institut de Recherche en Cancérologie de Montpellier (IRCM) , Montpellier, France .|2 INSERM , U1194, Montpellier, France .|3 Université de Montpellier , Montpellier, France .|4 Institut régional du Cancer de Montpellier , Montpellier, France .
authors.forename: Isabelle
authors.initials: I
authors.lastname: Navarro-Teulon
authors.affiliation: 6 Institute of Cancer Sciences, University of Glasgow , Glasgow, Scotland.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mairs
authors.affiliation: 1 Institut de Recherche en Cancérologie de Montpellier (IRCM) , Montpellier, France .|2 INSERM , U1194, Montpellier, France .|3 Université de Montpellier , Montpellier, France .|4 Institut régional du Cancer de Montpellier , Montpellier, France .
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pouget
mesh_terms: D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism* / Q000528:radiation effects*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004583:Electrons; D055786:Gene Knockout Techniques; D016158:Genes, p53; D045325:HCT116 Cells; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology; D007457:Iodine Radioisotopes / Q000009:adverse effects; D020935:MAP Kinase Signaling System; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D008954:Models, Biological; D018384:Oxidative Stress / Q000528:radiation effects*; D010750:Phosphoproteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D018796:Immunoconjugates; D007457:Iodine Radioisotopes; D010750:Phosphoproteins; D017382:Reactive Oxygen Species