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Apoptosis and p53 are not involved in the anti-tumor efficacy of (125)I-labeled monoclonal antibodies targeting the cell membrane.: Running title: 125I-RIT-induced cell death mechanisms

Abstract : INTRODUCTION: (125)I-labeled monoclonal antibodies ((125)I-mAbs) can efficiently treat small solid tumors. Here, we investigated the role of apoptosis, autophagy and mitotic catastrophe in (125)I-mAb toxicity in p53(-/-) and p53(+/+) cancer cells. METHODS: We exposed p53(-/-) and p53(+/+) HCT116 cells to increasing activities of internalizing (cytoplasmic location) anti-HER1 (125)I-mAbs, or non-internalizing (cell surface location) anti-CEA (125)I-mAbs. For each targeting model we established the relationship between survival and mean nucleus absorbed dose using the MIRD formalism. RESULTS: In both p53(-/-) and p53(+/+) HCT116 cells, anti-CEA (125)I-mAbs were more cytotoxic per Gy than anti-HER1 (125)I-mAbs. Sensitivity to anti-CEA (125)I-mAbs was p53-independent, while sensitivity to anti-HER1 (125)I-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 (125)I-mAbs. By contrast, mitotic death was similarly induced in both p53(-/-) and p53(+/+) HCT116 cells by the two types of (125)I-mAbs. We also showed using medium transfer experiments that γ-H2AX foci were produced in bystander cells. CONCLUSION: Cell membrane sensitivity to (125)I-mAbs is not mediated by apoptosis and is p53-independent. Bystander effects-mediated mitotic death could be involved in the efficacy of (125)I-mAbs binding cell surface receptors.
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https://www.hal.inserm.fr/inserm-00815724
Contributor : Yves Le Ster <>
Submitted on : Friday, April 19, 2013 - 11:49:55 AM
Last modification on : Friday, September 11, 2020 - 3:15:45 AM
Long-term archiving on: : Monday, April 3, 2017 - 7:46:16 AM

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Salomé Paillas, Vincent Boudousq, Bérengère Piron, Nathalie Kersual, Manuel Bardiès, et al.. Apoptosis and p53 are not involved in the anti-tumor efficacy of (125)I-labeled monoclonal antibodies targeting the cell membrane.: Running title: 125I-RIT-induced cell death mechanisms. Nuclear Medicine and Biology, Elsevier, 2013, epub ahead of print. ⟨10.1016/j.nucmedbio.2013.02.001⟩. ⟨inserm-00815724⟩

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