Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 71

Abstract

Platinum compounds are very effective anti‐cancer agents and act forming adducts with DNA and cytoplasmic proteins. Their main dose‐limiting side effect is peripheral neurotoxicity. Cisplatin neurotoxicity has been studied in many in vitro and in vivo models but little information is available for oxaliplatin. In this study we evaluated and compared the effect of cisplatin and oxaliplatin (a gift from Debiopharm S.A., Lausanne, Switzerland) in an in vitro model of neurotoxicity using the human neuroblastoma SH‐SY5Y cells, which may be considered as neuroblasts. Both platinum compounds are toxic and induce cellular death by apoptosis. Oxaliplatin is less neurotoxic than cisplatin. Concentrations of oxaliplatin 3–4 times higher than those of cisplatin are necessary to induce the same percentage of cellular death. We analyzed the activation/inactivation of specific molecules involved in the apoptotic transduction pathway. After exposure to both cisplatin and oxaliplatin the anti‐apoptotic protein Bcl‐2 was significantly reduced and thus could not exert its anti‐apoptotic action. Conversely, the pro‐apoptotic proteins p53, caspase 3, and caspase 7 were activated. In our experiments in SH‐SY5Y cells treated with cisplatin or oxaliplatin, the amount of p53 protein was markedly increased. In treated cultures, both caspase 3 and 7 were cleaved with the appearance of their active fragments which induced PARP cleavage. Our results suggest that neurotoxicity of cisplatin and oxaliplatin share a similar pathway. Neurotoxicity induced by platinum compounds is due not only to DNA damage but also to the activation of specific molecular pathways committing cells to apoptosis.