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

Title
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
Issue Date
2011
Journal Title
Toxicology in Vitro
ISSN
0887-2333
Citation
Toxicology in Vitro, Vol.25(7) : 1359~1365, 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://www.sciencedirect.com/science/article/pii/S0887233311001317

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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