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Apoptosis and p53 are not involved in the anti-tumor efficacy of 125I-labeled monoclonal antibodies targeting the cell membrane

2013; Elsevier BV; Volume: 40; Issue: 4 Linguagem: Inglês

10.1016/j.nucmedbio.2013.02.001

1872-9614

Salomé Paillas, Vincent Boudousq, Bérengère Piron, Nathalie Kersual, Manuel Bardiès, Nicolas Chouin, Caroline Mollévi, François‐Xavier Arnaud, André Pèlegrin, Isabelle Navarro‐Teulon, Jean‐Pierre Pouget,

Monoclonal and Polyclonal Antibodies Research

125I-labeled monoclonal antibodies (125I-mAbs) can efficiently treat small solid tumors. Here, we investigated the role of apoptosis, autophagy and mitotic catastrophe in 125I-mAb toxicity in p53−/− and p53+/+ cancer cells. We exposed p53−/− and p53+/+ HCT116 cells to increasing activities of internalizing (cytoplasmic location) anti-HER1 125I-mAbs, or non-internalizing (cell surface location) anti-CEA 125I-mAbs. For each targeting model we established the relationship between survival and mean nucleus absorbed dose using the MIRD formalism. In both p53−/− and p53+/+ HCT116 cells, anti-CEA 125I-mAbs were more cytotoxic per Gy than anti-HER1 125I-mAbs. Sensitivity to anti-CEA 125I-mAbs was p53-independent, while sensitivity to anti-HER1 125I-mAbs was higher in p53−/− HCT 116 cells, suggesting that they act through different signaling pathways. Apoptosis was only induced in p53+/+ HCT116 cells and could not explain cell membrane radiation sensitivity. Inhibition of autophagy did not modify the cell response to 125I-mAbs. By contrast, mitotic death was similarly induced in both p53−/− and p53+/+ HCT116 cells by the two types of 125I-mAbs. We also showed using medium transfer experiments that γ-H2AX foci were produced in bystander cells. Cell membrane sensitivity to 125I-mAbs is not mediated by apoptosis and is p53-independent. Bystander effects-mediated mitotic death could be involved in the efficacy of 125I-mAbs binding cell surface receptors.