PACAP prevents toxicity induced by cisplatin in rat and primate neurons but not in proliferating ovary cells: involvement of the mitochondrial apoptotic pathway.
Cisplatin is a chemotherapeutic agent whose use is limited by side effects including neuropathies. In proliferating cells, toxic action of cisplatin is based on DNA interactions, while, in quiescent cells, it can induce apoptosis by interacting with proteins. In the present study, we compared cytotoxic mechanisms activated by cisplatin in primate and rodent neurons and in ovary cells in order to determine whether the anti-apoptotic peptide PACAP could selectively reduce neurotoxicity. In quiescent neurons, JNK and sphingomyelinase inhibitors blocked cisplatin-induced cell death. Toxicity was associated with DNA laddering, caspase-3 and -9 activations and Bax induction. These effects were prevented by PACAP. In proliferating cells, cisplatin activated caspase-8 but had no effect on caspase-9. PACAP exerted no protective effect. These data indicate that cisplatin activates distinct apoptotic pathways in quiescent neurons and proliferating cells and that PACAP may reduce neurotoxicity of cisplatin without affecting its chemotherapeutic efficacy.
Aubert
Nicolas
N
INSERM U413, Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research (IFRMP 23), University of Rouen, Mont-Saint-Aignan, France.
Vaudry
David
D
Falluel-Morel
Anthony
A
Desfeux
Arnaud
A
Fisch
Cécile
C
Ancian
Philippe
P
de Jouffrey
Stéphane
S
Le Bigot
Jean-François
JF
Couvineau
Alain
A
Laburthe
Marc
M
Fournier
Alain
A
Laudenbach
Vincent
V
Vaudry
Hubert
H
Gonzalez
Bruno J
BJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D016466:CHO Cells; D002144:Callithrix; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000627:therapeutic use / Q000633:toxicity; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D024101:Mitochondrial Proteins / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D010053:Ovary / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; D024101:Mitochondrial Proteins; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D002945:Cisplatin