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Inhibition of caspase-dependent mitochondrial permeability transition protects airway epithelial cells against mustard-induced apoptosis

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Abstract

In the present study, the toxicity of yperite, SM, and its structural analogue mechlorethamine, HN2, was investigated in a human bronchial epithelial cell line 16HBE. Cell detachment was initiated by caspase-2 activation, down-regulation of Bcl-2 and loss of mitochondrial membrane potential. Only in detached cells, mustards induced apoptosis associated with increase in p53 expression, Bax activation, decrease in Bcl-2 expression, opening of the mitochondrial permeability transition pore, release of cytochrome c, caspase-2, -3, -8, -9 and -13 activation and DNA fragmentation. Apoptosis, occurring only in detached cells, could be recognized as anoikis and the mitochondrion, involved both in cell detachment and subsequent cell death, appears to be a crucial checkpoint. Based on our understanding of the apoptotic pathway triggered by mustards, we demonstrated that inhibition of the mitochondrial pathway by ebselen, melatonin and cyclosporine A markedly prevented mustard-induced anoikis, pointing to these drugs as interesting candidates for the treatment of mustard-induced airway epithelial lesions.

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Authors and Affiliations

  1. Laboratoire de Cytophysiologie et Toxicologie Cellulaire, Université Paris 7-Denis Diderot, case 70-73, 2 place Jussieu, 75251, Paris Cedex 05, France

    Matthieu Sourdeval, Emmanuelle Boisvieux-Ulrich & Francelyne Marano

  2. Laboratoire de Génétique et Biologie Cellulaire, Université de Versailles/St Quentin, CNRS FRE 2445, France

    Christophe Lemaire, Aurélien Deniaud & Catherine Brenner

  3. Centre d’Etudes du Bouchet, Délégation Générale pour l’Armement, France

    Laurent Taysse, Sébastien Daulon & Patrick Breton

Authors
  1. Matthieu Sourdeval
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  2. Christophe Lemaire
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  3. Aurélien Deniaud
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  4. Laurent Taysse
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  5. Sébastien Daulon
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  6. Patrick Breton
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  7. Catherine Brenner
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  8. Emmanuelle Boisvieux-Ulrich
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  9. Francelyne Marano
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Correspondence to Matthieu Sourdeval.

Additional information

This work was support by the Délégation Générale pour l’Armement (D.G.A./D.S.P. No. 95-151). A. Deniaud received a fellowship from Ligue contre le Cancer. C. Brenner is supported by the Association pour la Recherche sur le Cancer (ARC). The authors are grateful to D.C. Gruenert for providing us with the human bronchial epithelial cell line.

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Sourdeval, M., Lemaire, C., Deniaud, A. et al. Inhibition of caspase-dependent mitochondrial permeability transition protects airway epithelial cells against mustard-induced apoptosis. Apoptosis 11, 1545–1559 (2006). https://doi.org/10.1007/s10495-006-8764-1

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