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 fac tor in cisplatin chemotherapy of cancer patients. We investigated the patho mechanism underlying cisplatin neuropathy using a mouse dorsal root ganglio n 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, Pas , and Fas ligand (Fas-L) was also demonstrated in these neurons. Preincubat ion with N-acetylcysteine (NAC), a precursor of glutathione, blocked cispla tin-induced apoptosis completely, whereas Trolox, a vitamin E analogue, blo cked it partially, Cisplatin-induced p53 accumulation was suppressed by NAC treatment, whereas p53 accumulation was retarded by Trolox treatment. In c ontrast, neither NAC nor Trolox showed any inhibitory effect on cisplatin-i nduced Fas/Fas-L accumulation. These results suggest that the neuroprotecti ve effects of antioxidants against cisplatin-induced neurotoxicity in hybri d neurons are mediated mainly through the inhibition of p53 accumulation bu t not of Fas/ Fas-L accumulation by these antioxidants.