Role of MAPKs in platinum-induced neuronal apoptosis.
An unsolved question is how platinum derivatives used for solid cancer therapy cause peripheral neuropathy in patients and apoptosis in "in vitro" models of chemotherapy-induced peripheral neuropathy. DRG neurons from E15 rat embryos were treated with toxic doses of oxaliplatin or cisplatin. Here, the role of MAPKs in neuronal apoptosis was studied. Both oxaliplatin and cisplatin induced a dose-dependent neuronal apoptosis, modulated by the proteins of Bcl-2 family. Regarding MAPKs, platinum derivatives activated p38 while they reduced the active form and the total amount of JNK/Sapk. Both oxaliplatin and cisplatin activated ERKs at early stages, although they behaved differently at later stages. By using specific inhibitors of the various MAPKs it was demonstrated that the platinum-induced neuronal apoptosis is mediated by early p38 and ERK1/2 activation, while JNK/Sapk has a neuroprotective role. These results suggest a role for the different MAPKs in peripheral neuropathies characterized by apoptosis of DRG neurons.
Dipartimento di Neuroscienze e Tecnologie Biomediche, Università degli Studi di Milano-Bicocca, Monza, Italy. arianna.scuteri@unimib.it
Arianna
A
Scuteri
Alessia
A
Galimberti
Daniele
D
Maggioni
Maddalena
M
Ravasi
Silvia
S
Pasini
Gabriella
G
Nicolini
Mario
M
Bossi
Mariarosaria
M
Miloso
Guido
G
Cavaletti
Giovanni
G
Tredici
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D010984:Platinum / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D010984:Platinum; D020928:Mitogen-Activated Protein Kinases