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

摘要

>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. Antioxid. Redox Signal. 25, 467–484.