title: Characterization of and protection from neurotoxicity induced by oxaliplatin, bortezomib and epothilone-B.
abstract: OBJECTIVE
  To characterize neurotoxicity induced by oxaliplatin, bortezomib, and epothilone-B as well as protection against their neurotoxicity using an in vitro model.
  
  
  METHODS
  Neurotoxicity was evaluated using the neurite outgrowth method in PC12 rat pheochromo-cytoma cells differentiated towards a mature neuronal phenotype, while neuroprotection was explored by simultaneous exposure to 0.5 mM amifostine. The potential markers of neuronal differentiation, cyclin-B2 (Ccnb2) and baculoviral inhibitor of apoptosis repeat-containing 5 (Birc5), were evaluated by quantitative reverse transcription polymerase chain reaction (RT-PCR).
  
  
  RESULTS
  Bortezomib, epothilone-B, and oxaliplatin reduced neurite length to 68%, 78% and 66%, respectively (p<0.05). The percentage of neurite-forming-cells (discriminating neurotoxicity from general cytotoxicity) decreased from 70% (control) to 55% (bortezomib), 46% (epothilone-B), and 51% (oxaliplatin). Amifostine was neuroprotective against oxaliplatin-induced neurotoxicity, increasing both neurite length and neurite-forming-cells. Quantitative-RT-PCR showed a 2.7-fold decrease in Ccnb2 expression in differentiated PC12 vs. undifferentiated cells.
  
  
  CONCLUSIONS
  Oxaliplatin, bortezomib, and epothilone-B are neurotoxic in the PC12 model. Amifostine has a neuroprotective effect only against oxaliplatin-induced neurotoxicity, suggesting that these compounds have different mechanisms of neurotoxicity.
authors.affiliation: Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands. elisa.giovannetti@gmail.com, gj.peters@vumc.nl.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Ceresa
authors.forename: Abolfazl
authors.initials: A
authors.lastname: Avan
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovannetti
authors.forename: Albert A
authors.initials: AA
authors.lastname: Geldof
authors.forename: Amir
authors.initials: A
authors.lastname: Avan
authors.forename: Guido
authors.initials: G
authors.lastname: Cavaletti
authors.forename: Godefridus J
authors.initials: GJ
authors.lastname: Peters
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D004999:Amifostine / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000633:toxicity*; D000069286:Bortezomib; D002454:Cell Differentiation / Q000187:drug effects; D056765:Cyclin B2 / Q000235:genetics / Q000378:metabolism; D034261:Epothilones / Q000633:toxicity*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000473:pathology*; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000517:prevention & control*; D009944:Organoplatinum Compounds / Q000633:toxicity*; D000077150:Oxaliplatin; D010673:Pheochromocytoma / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D011719:Pyrazines / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics; D011837:Radiation-Protective Agents / Q000627:therapeutic use; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C516989:Birc5 protein, rat; D001897:Boronic Acids; C503761:Ccnb2 protein, rat; D056765:Cyclin B2; D034261:Epothilones; D008869:Microtubule-Associated Proteins; D009944:Organoplatinum Compounds; D011719:Pyrazines; D012333:RNA, Messenger; D011837:Radiation-Protective Agents; D000077022:Survivin; D000077150:Oxaliplatin; D000069286:Bortezomib; D004999:Amifostine; C093788:epothilone B
keywords: Neurotoxicity; PC12 model; amifostine neuroprotection; cyclin-B2; oxaliplatin