Cisplatin-induced apoptotic cell death in mouse hybrid neurons is blocked by antioxidants through suppression of cisplatin-mediated accumulation of p53 but not of Fas/Fas ligand.
Peripheral neuropathy following cisplatin treatment is a major limiting factor in cisplatin chemotherapy of cancer patients. We investigated the pathomechanism underlying cisplatin neuropathy using a mouse dorsal root ganglion neuron-neuroblastoma hybrid cell line (N18D3) developed in our laboratory. DNA fragmentation, a characteristic feature of apoptosis, was induced in hybrid neurons following treatment with cisplatin. Accumulation of p53, Fas, and Fas ligand (Fas-L) was also demonstrated in these neurons. Preincubation with N-acetylcysteine (NAC), a precursor of glutathione, blocked cisplatin-induced apoptosis completely, whereas Trolox, a vitamin E analogue, blocked it partially. Cisplatin-induced p53 accumulation was suppressed by NAC treatment, whereas p53 accumulation was retarded by Trolox treatment. In contrast, neither NAC nor Trolox showed any inhibitory effect on cisplatin-induced Fas/Fas-L accumulation. These results suggest that the neuroprotective effects of antioxidants against cisplatin-induced neurotoxicity in hybrid neurons are mediated mainly through the inhibition of p53 accumulation but not of Fas/Fas-L accumulation by these antioxidants.
Park
S A
SA
Department of Neurology, Ajou University School of Medicine, Suwon, Korea.
Choi
K S
KS
Bang
J H
JH
Huh
K
K
Kim
S U
SU
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D053938:DNA Fragmentation; D053222:Fas Ligand Protein; D005727:Ganglia, Spinal; D006822:Hybrid Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D009447:Neuroblastoma; D009475:Neurons, Afferent / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
D000975:Antioxidants; D002839:Chromans; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D002945:Cisplatin; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D000111:Acetylcysteine