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Carmustine induces ERK- and JNK-dependent cell death of neuronally-differentiated PC12 cells via generation of reactive oxygen species

 Jeong Mi An  ;  Seon Sook Kim  ;  Jin Hak Rhie  ;  Dong Min Shin  ;  Su Ryeon Seo  ;  Jeong Taeg Seo 
 TOXICOLOGY IN VITRO, Vol.25(7) : 1359-1365, 2011 
Journal Title
Issue Date
Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents, Alkylating/pharmacology ; Carmustine/pharmacology* ; Caspase 3/metabolism ; Cell Death/drug effects ; Enzyme Activation ; Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors ; Extracellular Signal-Regulated MAP Kinases/genetics ; Extracellular Signal-Regulated MAP Kinases/metabolism* ; Glutathione Reductase/antagonists & inhibitors ; MAP Kinase Kinase 4/antagonists & inhibitors ; MAP Kinase Kinase 4/genetics ; MAP Kinase Kinase 4/metabolism* ; Neurons/cytology ; Neurons/drug effects* ; PC12 Cells ; Phosphorylation ; Rats ; Reactive Oxygen Species/metabolism* ; p38 Mitogen-Activated Protein Kinases/genetics ; p38 Mitogen-Activated Protein Kinases/metabolism
Carmustine ; Reactive oxygen species ; ERK ; JNK
Accumulation of reactive oxygen species (ROS) caused by the inhibition of glutathione reductase (GR) has been proposed as one of the mechanisms responsible for carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, BCNU)-induced cytotoxicity. Since mitogen-activated protein kinases (MAPKs) are known to mediate ROS-dependent cell death in multiple cell types, we examined whether redox-sensitive MAPK activation mediated the carmustine-induced cell death of neuronally differentiated PC12 cells. Carmustine induced a concentration- and time-dependent cell death, which was associated with increased caspase-3 activation, a reduction in GR activity accompanied by a concomitant decrease in reduced glutathione levels, and accumulation of ROS. Carmustine-induced caspase-3 activation and cell death were prevented by pretreatment with anti-oxidants or a reducing agent, indicating that carmustine-induced caspase-3 activation and cell death occur via redox-dependent processes. Carmustine induced phosphorylation of the MAPKs, such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. The activation of these kinases was inhibited by pretreatment with N-acetyl-L-cysteine (NAC). Although all the MAPKs were activated by carmustine, only the inhibitors of JNK and ERK prevented carmustine-induced cell death and caspase-3 activation. Our data suggest that carmustine-induced neurotoxicity is, at least in part, due to the activation of ROS-dependent JNK and ERK signaling.
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2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Seo, Jeong Taeg(서정택) ORCID logo https://orcid.org/0000-0003-2697-0251
Shin, Dong Min(신동민) ORCID logo https://orcid.org/0000-0001-6042-0435
An, Jeong Mi(안정미)
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