Neurotoxicity of Platinum Compounds: Comparison of the Effects of Cisplatin and Oxaliplatin on the Human Neuroblastoma Cell Line SH-SY5Y
The main dose-limiting side effect of cancer treatment with platinum compounds is peripheral neurotoxicity. To investigate the intracellular mechanisms of platinum drugs neurotoxicity we have studied the effects of cisplatin and oxaliplatin on the human neuroblastoma cell line SH-SY5Y. Both platinum compounds are toxic causing cellular death by inducing apoptosis but oxaliplatin is less neurotoxic than cisplatin. The study of the proteins involved in the intracellular transduction pathways that may cause apoptotic death, revealed a very similar pattern of changes after exposure to cisplatin or oxaliplatin. In particular, as demonstrated by densitometric analysis, after exposure to both platinum compounds the total amount of the anti-apoptotic protein Bcl-2 was significantly reduced. Conversely, the amount of the pro-apoptotic protein p53 significantly increased. Caspases 3 and 7 were activated, but their activation was a late event, indicating a secondary role in the apoptotic process. Among the mitogen activated protein kinases, only the p38 protein was activated (phosphorylated) early enough to have a possible role in inducing apoptosis, possibly through p53 stabilization. The results of the present study and the data of the literature demonstrate that the ways in which cisplatin and oxaliplatin are neurotoxic are very similar and include not only DNA damage, but also the modulation of specific molecules involved in regulating the cellular equilibrium between apoptotic death and the cell cycle.
Unable to display preview. Download preview PDF.
- 10.Gill JS, Windebank AJ: Cisplatin-induced apoptosis in rat dorsal root ganglion neurons is associated with attempted entry into the cell cycle. J Clin Invest 101: 2442–2450, 1998Google Scholar
- 13.Casciolo-Rosen L, Nicholson DW, Chong T, Rowan KR, Thornberry NA, Miller DK, Rosen A: Apopain/CPP32 cleaves proteins that are essential for cellular repair: a fundamental principle of apoptotic death. J Exp Med 183: 1957–1964, 1996Google Scholar
- 26.Haldar S, Jena N, Croce CM: Inactivation of Bcl-2 by phosphorylation. Proc Natl Acad Sci USA 92: 4507–4511, 1995Google Scholar
- 43.Helmuth A, Stefan Q, Julian G, Alexandra L, Florian E, Christian L: The chemotherapeutic oxaliplatin alters voltage-gated Na SUP + channel kinetics on rat sensory neurons. Eur J Pharmacol 406: 25–32, 2000Google Scholar