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Neurotoxicity of platinum compounds:
comparison of the effects of cisplatin and oxaliplatin on the human
neuroblastoma cell line SH-SY5Y
Elisabetta Donzelli, Maria Carfì,
Mariarosaria Miloso, Alberto Strada, Stefania Galbiati, Martine
Bayssas, Genevieve Griffon-Etienne, Guido Cavaletti, Maria Grazia Petruccioli
and Giovanni Tredici
Dipartimento di Neuroscienze
e Tecnologie Biomediche, Università degli Studi di Milano-Bicocca, Monza, Italy
(E.D., M.C., M.M., A.S., S.G., G.C., G.T.); Debiopharm S.A., Lausanne,
Switzerland (M.B., G.G.-E.); Clinica Neurologica, Ospedale San Gerardo, Monza
(G.C.); Dipartimento di Anatomia Umana, Università degli Studi di Milano,
Milano, Italy (M.G.P.)
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.
PMID: 15072449 [PubMed]
Source: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15072449
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