Inhibition of caspase-dependent mitochondrial permeability transition protects airway epithelial cells against mustard-induced apoptosis |
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Authors: | Matthieu Sourdeval Christophe Lemaire Aurélien Deniaud Laurent Taysse Sébastien Daulon Patrick Breton Catherine Brenner Emmanuelle Boisvieux-Ulrich Francelyne Marano |
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Institution: | (1) Laboratoire de Cytophysiologie et Toxicologie Cellulaire, Université Paris 7-Denis Diderot, case 70-73, 2 place Jussieu, 75251 Paris Cedex 05, France;(2) Laboratoire de Génétique et Biologie Cellulaire, Université de Versailles/St Quentin, CNRS FRE 2445, France;(3) Centre d’Etudes du Bouchet, Délégation Générale pour l’Armement, France |
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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.
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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Keywords: | Anoikis Caspase-2 Mitochondria Respiratory tract Sulfur mustard Therapeutics |
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