Induction of cellular necrosis by the glutathione peroxidase mimetic ebselen.
The selenium-based compound ebselen is a powerful antioxidant, a potent anti-inflammatory agent and a potential neuroprotective compound. Several studies have demonstrated that part of the biological effect of ebselen is the result of the inhibition of apoptosis. We show in this report that ebselen induced the necrotic cell death of Sp2/0-Ag14 hybridoma cells. This process was rapid, with over 90% of the cells being dead after a 2 h exposure to 50 microM ebselen. The toxic effect of ebselen could not be prevented by the caspase inhibitor Z-VAD-fmk but could be blocked with thiol-containing compounds. Interestingly, ebselen addition completely prevented caspase activation in cycloheximide-treated Sp2/O-Ag14 cells, indicating that this antioxidant interferes with the apoptotic machinery. Our results indicate that some cell types are acutely sensitive to the toxic effect of ebselen, and that ebselen-induced cell death interferes with apoptotic processes. These observations are of particular importance since ebselen is currently used in clinical trials for possible use as therapeutic agent for stroke.
Guérin
Paul J
PJ
Cellular Biochemistry Research Laboratory, Department of Chemistry-Biochemistry, Laurentian University, Sudbury, Ontario, Canada, P3E 2C6.
Gauthier
Eric R
ER
D000111:Acetylcysteine / Q000494:pharmacology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001393:Azoles / Q000633:toxicity*; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003513:Cycloheximide / Q000633:toxicity; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000378:metabolism*; D006825:Hybridomas; D054833:Isoindoles; D051379:Mice; D009336:Necrosis; D016566:Organoselenium Compounds / Q000633:toxicity*
D000590:Amino Acid Chloromethyl Ketones; D000975:Antioxidants; D001393:Azoles; D015853:Cysteine Proteinase Inhibitors; D054833:Isoindoles; D016566:Organoselenium Compounds; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C042986:ebselen; D003513:Cycloheximide; D005979:Glutathione Peroxidase; D020169:Caspases; D000111:Acetylcysteine