Inhibition of caspase-dependent mitochondrial permeability transition protects airway epithelial cells against mustard-induced apoptosis.
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.
Sourdeval
Matthieu
M
Labortoire de Cytophysiologie et Toxicologie Cellulaire, Université Paris 7-Denis Diderot, case 70-73, 2 place Jussieu, 75251 Paris Cedex 05, France. msourdeval@paris7.jussieu.fr
Lemaire
Christophe
C
Deniaud
Aurélien
A
Taysse
Laurent
L
Daulon
Sébastien
S
Breton
Patrick
P
Brenner
Catherine
C
Boisvieux-Ulrich
Emmanuelle
E
Marano
Francelyne
F
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001393:Azoles / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D054833:Isoindoles; D008466:Mechlorethamine / Q000633:toxicity; D008550:Melatonin / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D009151:Mustard Gas / Q000633:toxicity*; D016566:Organoselenium Compounds / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D001393:Azoles; D054833:Isoindoles; D046912:Multiprotein Complexes; D016566:Organoselenium Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; C042986:ebselen; D008466:Mechlorethamine; D016572:Cyclosporine; D020169:Caspases; D008550:Melatonin; D009151:Mustard Gas