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

Authors
 Jeong Mi An ; Seon Sook Kim ; Jeong Taeg Seo ; Su Ryeon Seo ; Dong Min Shin ; Jin Hak Rhie 
Citation
 Toxicology in Vitro, Vol.25(7) : 1359~1365, 2011 
Journal Title
 Toxicology in Vitro 
ISSN
 0887-2333 
Issue Date
2011
Abstract
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.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/93646
DOI
10.1016/j.tiv.2011.05.006
Appears in Collections:
1. 연구논문 > 2. College of Dentistry > Dept. of Oral Biology
Yonsei Authors
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Link
 http://www.sciencedirect.com/science/article/pii/S0887233311001317
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