Localized Irradiation of Cell Membrane by Auger Electrons Is Cytotoxic Through Oxidative Stress-Mediated Nontargeted Effects

Salomé Paillas (1, 2, 3) , Riad Ladjohounlou (1, 2) , Catherine Lozza (1, 2) , Alexandre Pichard (1, 2) , Vincent Boudousq (1, 2, 4) , Marta Jarlier (2) , Samuel Sevestre (1, 2) , Marion Le Blay (1, 2) , Emmanuel Deshayes (1, 2) , Jane Sosabowski (3) , Thierry Chardès (1, 2) , Isabelle Navarro-Teulon (1, 2) , Robert Mairs (5) , Jean-Pierre Pouget (1, 2)

1 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
2 ICM - UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle
3 QMUL - Queen Mary University of London
4 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
5 University of Glasgow

AIMS: 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]). RESULTS: 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. INNOVATION: 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. CONCLUSION: Our findings describe the mechanisms involved in the efficacy of (125)I-mAbs targeting the cancer cell surface. Antioxid. Redox Signal. 25, 467-484.

Domaines: Biochimie [q-bio.BM]; Biologie moléculaire; Endocrinologie et métabolisme

Salomé Paillas, Riad Ladjohounlou, Catherine Lozza, Alexandre Pichard, Vincent Boudousq, et al.. Localized Irradiation of Cell Membrane by Auger Electrons Is Cytotoxic Through Oxidative Stress-Mediated Nontargeted Effects. Antioxidants and Redox Signaling, 2016, 25 (8), pp.467 - 484. ⟨10.1089/ars.2015.6309⟩. ⟨hal-01905223⟩