Localized irradiation of cell membrane by Auger electrons Is cytotoxic through oxidative stress-mediated nontargeted effects

Paillas, S. et al. (2016) Localized irradiation of cell membrane by Auger electrons Is cytotoxic through oxidative stress-mediated nontargeted effects. Antioxidants and Redox Signaling, 25(8), pp. 467-484. (doi: 10.1089/ars.2015.6309) (PMID:27224059) (PMCID:PMC5028911)

Abstract

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 125I [125I-mAbs]). Results: We showed that the cytotoxicity of 125I-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. 125I-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 Ca2+ fluxes. Moreover, the nontargeted response induced by directing 5-[(125)I]iodo-2′-deoxyuridine to the nucleus was comparable to that of 125I-mAb against cell surface receptors. In vivo, we found that the statistical significance of tumor growth delay induced by 125I-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 125I, 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 125I-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 125I-mAbs targeting the cancer cell surface.

• Item Type: Articles
• Additional Information: This work was supported by Action Nu1.1 of Plan Cancer 2009–2013 (ASC 13038FSA), by the French National Research Agency under the program ‘‘Investissements d’avenir’’ Grant agreement LabEx MAbImprove: ANR-10- LABX-53, Grant INCa-DGOS-Inserm 6045, and the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007–2013) under REA grant agreement No. 608765 and Marie Curie WHRI Academy COFUND programme.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Mairs, Professor Robert
• Authors: Paillas, S., Ladjohounlou, R., Lozza, C., Pichard, A., Boudousq, V., Jarlier, M., Sevestre, S., Le Blay, M., Deshayes, E., Sosabowski, J., Chardès, T., Navarro-Teulon, I., Mairs, R. J., and Pouget, J.-P.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Antioxidants and Redox Signaling
• Publisher: Mary Ann Liebert
• ISSN: 1523-0864
• ISSN (Online): 1557-7716
• Published Online: 25 May 2016
• Copyright Holders: Copyright © 2016 Salomé Paillas, et al
• First Published: First published in Antioxidants and Redox Signaling 25(8): 467-484
• Publisher Policy: Reproduced under a Creative Commons License