Caspase inhibitors prevent cisplatin-induced apoptosis of auditory sensory cells.
In vitro studies tested the efficacy of three caspase inhibitors, Ac-VAD-cmk (caspase-1 inhibitor), z-DEVD-fmk (caspase-3 inhibitor) and B-D-fmk (BOCDFK, a general inhibitor), for protecting auditory sensory cells from cisplatin-damage induced loss. Treatment of 3-day-old rat organ of Corti explants with these caspase inhibitors protected > 80% of the auditory hair cells from cisplatin-damage initiated apoptosis. Dissociated cell cultures of 3-day-old rat spinal ganglia treated with any of these three caspase inhibitors in addition to exogenous neurotrophin have highly significant increases in neuronal survival following cisplatin exposure. These results indicate that loss of auditory sensory cells as a result of cisplatin-induced damage involves apoptosis and that blocking of this cell death pathway at the caspase level effectively rescues both hair cells and neurons.
Department of Otolaryngology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
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Liu
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Staecker
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Stupak
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Malgrange
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Lefebvre
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Van De Water
D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D061945:Caspase Inhibitors; D002452:Cell Count / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006198:Hair Cells, Auditory / Q000187:drug effects; D006309:Hearing / Q000187:drug effects / Q000502:physiology; D020287:In Situ Nick-End Labeling; D009475:Neurons, Afferent / Q000187:drug effects*; D009925:Organ of Corti / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; C505410:Casp3 protein, rat; D053148:Caspase 3; D002945:Cisplatin