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

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Abstract
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.