| Added by | liaudet-coopman |
|---|---|
| Last modified by | tchardes |
| Group name | EquipeELC |
| Item Type | Journal Article |
| Title | Localized Irradiation of Cell Membrane by Auger Electrons Is Cytotoxic Through Oxidative Stress-Mediated Nontargeted Effects |
| Creator | Paillas et al. |
| Author | Salomé Paillas |
| Author | Riad Ladjohounlou |
| Author | Catherine Lozza |
| Author | Alexandre Pichard |
| Author | Vincent Boudousq |
| Author | Marta Jarlier |
| Author | Samuel Sevestre |
| Author | Marion Le Blay |
| Author | Emmanuel Deshayes |
| Author | Jane Sosabowski |
| Author | Thierry Chardès |
| Author | Isabelle Navarro-Teulon |
| Author | Robert J. Mairs |
| Author | Jean-Pierre Pouget |
| 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 (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-?-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-? (PLC-?), 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. |
| Publication | Antioxidants & Redox Signaling |
| Volume | 25 |
| Issue | 8 |
| Pages | 467-484 |
| Date | 09 10, 2016 |
| Journal Abbr | Antioxid. Redox Signal. |
| Language | eng |
| DOI | 10.1089/ars.2015.6309 |
| ISSN | 1557-7716 |
| Library Catalog | PubMed |
| Extra | PMID: 27224059 PMCID: PMC5028911 |
| Tags | Cell Line, Tumor, Cell Membrane, Cell Survival, cnrs, Electrons, Gene Knockout Techniques, Genes, p53, HCT116 Cells, Humans, Immunoconjugates, Iodine Radioisotopes, MAP Kinase Signaling System, Membrane Microdomains, Models, Biological, original, Oxidative Stress, Phosphoproteins, Reactive Oxygen Species |
| Date Added | 2019/05/29 - 12:58:38 |
| Date Modified | 2023/04/06 - 16:51:34 |
| Notes and Attachments | PubMed entry (Attachment) Texte intégral (Attachment) |
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