title: PACAP prevents toxicity induced by cisplatin in rat and primate neurons but not in proliferating ovary cells: involvement of the mitochondrial apoptotic pathway.
abstract: 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.
authors.affiliation: INSERM U413, Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research (IFRMP 23), University of Rouen, Mont-Saint-Aignan, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Aubert
authors.forename: David
authors.initials: D
authors.lastname: Vaudry
authors.forename: Anthony
authors.initials: A
authors.lastname: Falluel-Morel
authors.forename: Arnaud
authors.initials: A
authors.lastname: Desfeux
authors.forename: Cécile
authors.initials: C
authors.lastname: Fisch
authors.forename: Philippe
authors.initials: P
authors.lastname: Ancian
authors.forename: Stéphane
authors.initials: S
authors.lastname: de Jouffrey
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Le Bigot
authors.forename: Alain
authors.initials: A
authors.lastname: Couvineau
authors.forename: Marc
authors.initials: M
authors.lastname: Laburthe
authors.forename: Alain
authors.initials: A
authors.lastname: Fournier
authors.forename: Vincent
authors.initials: V
authors.lastname: Laudenbach
authors.forename: Hubert
authors.initials: H
authors.lastname: Vaudry
authors.forename: Bruno J
authors.initials: BJ
authors.lastname: Gonzalez
mesh_terms: 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
chemical_list: D051017:Apoptosis Regulatory Proteins; D024101:Mitochondrial Proteins; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D002945:Cisplatin