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, DongMin Shin, Su Ryeon Seo, Jeong Taeg Seo

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1359-1365
Number of pages7
JournalToxicology in Vitro
Volume25
Issue number7
DOIs
Publication statusPublished - 2011 Oct 1

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Carmustine
PC12 Cells
Extracellular Signal-Regulated MAP Kinases
Cell death
Reactive Oxygen Species
Cell Death
Phosphotransferases
Chemical activation
Mitogen-Activated Protein Kinases
Caspase 3
Glutathione Reductase
Oxidation-Reduction
Acetylcysteine
Phosphorylation
JNK Mitogen-Activated Protein Kinases
Reducing Agents
Cytotoxicity
Oxidants
Glutathione
Cysteine

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

An, Jeong Mi ; Kim, Seon Sook ; Rhie, Jin Hak ; Shin, DongMin ; Seo, Su Ryeon ; Seo, Jeong Taeg. / Carmustine induces ERK- and JNK-dependent cell death of neuronally-differentiated PC12 cells via generation of reactive oxygen species. In: Toxicology in Vitro. 2011 ; Vol. 25, No. 7. pp. 1359-1365.
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Carmustine induces ERK- and JNK-dependent cell death of neuronally-differentiated PC12 cells via generation of reactive oxygen species. / An, Jeong Mi; Kim, Seon Sook; Rhie, Jin Hak; Shin, DongMin; Seo, Su Ryeon; Seo, Jeong Taeg.

In: Toxicology in Vitro, Vol. 25, No. 7, 01.10.2011, p. 1359-1365.

Research output: Contribution to journalArticle

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T1 - Carmustine induces ERK- and JNK-dependent cell death of neuronally-differentiated PC12 cells via generation of reactive oxygen species

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