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Novel biphasic effect of pyrrolidine dithiocarbamate on neuronal cell viability is mediated by the differential regulation of intracellular zinc and copper ion levels, NF-kappaB, and MAP kinases.
J Neurosci Res. 2000 Jan 01; 59(1):117-25.JN

Abstract

Nuclear factor kappaB (NF-kappaB) is a transcription factor involved in the expression of a wide range of genes, most of which code for proteins that play a role in immunity and inflammation. Pyrrolidine dithiocarbamate (PDTC) is a well-known inhibitor of NF-kappaB. Although its mechanism of action is conferred by its antioxidant property, other mechanisms by which PDTC can act as a prooxidant, metal chelator, and free thiol group modulator have recently been suggested. Here we report that PDTC caused a dual effect on cell viability in neuronal rat pheochromocytoma (PC12) cells, depending on its concentration. Increase of intracellular zinc and copper ion levels selectively potentiated the cytotoxic PDTC effect in a dose-dependent manner, and thiol reagents, such as glutathione and N-acetylcysteine, as well as divalent metal-chelating reagents, such as EDTA and bathocuproline disulfonic acid, blocked its cell death effect. The differential effect of PDTC on cell viability correlates well with the inhibition of NF-kappaB activities. In addition, PDTC differentially activated microtubule-associated protein (MAP) kinases, such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), but not p38, depending on its dose, and the coaddition of glutathione (GSH), other antioxidants, and metal ions also modulated their activities. Furthermore, stable Bcl-2 expression blocked the PDTC-induced cell death. These results suggest that the thiol groups and free zinc and copper ion levels are important for the novel biphasic PDTC effect on cell viability, which is associated with the differential activation of NF-kappaB and MAP kinases.

Authors+Show Affiliations

Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea. kchung@yumc.yonsei.ac.krNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10658192

Citation

Chung, K C., et al. "Novel Biphasic Effect of Pyrrolidine Dithiocarbamate On Neuronal Cell Viability Is Mediated By the Differential Regulation of Intracellular Zinc and Copper Ion Levels, NF-kappaB, and MAP Kinases." Journal of Neuroscience Research, vol. 59, no. 1, 2000, pp. 117-25.
Chung KC, Park JH, Kim CH, et al. Novel biphasic effect of pyrrolidine dithiocarbamate on neuronal cell viability is mediated by the differential regulation of intracellular zinc and copper ion levels, NF-kappaB, and MAP kinases. J Neurosci Res. 2000;59(1):117-25.
Chung, K. C., Park, J. H., Kim, C. H., Lee, H. W., Sato, N., Uchiyama, Y., & Ahn, Y. S. (2000). Novel biphasic effect of pyrrolidine dithiocarbamate on neuronal cell viability is mediated by the differential regulation of intracellular zinc and copper ion levels, NF-kappaB, and MAP kinases. Journal of Neuroscience Research, 59(1), 117-25.
Chung KC, et al. Novel Biphasic Effect of Pyrrolidine Dithiocarbamate On Neuronal Cell Viability Is Mediated By the Differential Regulation of Intracellular Zinc and Copper Ion Levels, NF-kappaB, and MAP Kinases. J Neurosci Res. 2000 Jan 1;59(1):117-25. PubMed PMID: 10658192.
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TY - JOUR T1 - Novel biphasic effect of pyrrolidine dithiocarbamate on neuronal cell viability is mediated by the differential regulation of intracellular zinc and copper ion levels, NF-kappaB, and MAP kinases. AU - Chung,K C, AU - Park,J H, AU - Kim,C H, AU - Lee,H W, AU - Sato,N, AU - Uchiyama,Y, AU - Ahn,Y S, PY - 2000/2/5/pubmed PY - 2000/3/4/medline PY - 2000/2/5/entrez SP - 117 EP - 25 JF - Journal of neuroscience research JO - J Neurosci Res VL - 59 IS - 1 N2 - Nuclear factor kappaB (NF-kappaB) is a transcription factor involved in the expression of a wide range of genes, most of which code for proteins that play a role in immunity and inflammation. Pyrrolidine dithiocarbamate (PDTC) is a well-known inhibitor of NF-kappaB. Although its mechanism of action is conferred by its antioxidant property, other mechanisms by which PDTC can act as a prooxidant, metal chelator, and free thiol group modulator have recently been suggested. Here we report that PDTC caused a dual effect on cell viability in neuronal rat pheochromocytoma (PC12) cells, depending on its concentration. Increase of intracellular zinc and copper ion levels selectively potentiated the cytotoxic PDTC effect in a dose-dependent manner, and thiol reagents, such as glutathione and N-acetylcysteine, as well as divalent metal-chelating reagents, such as EDTA and bathocuproline disulfonic acid, blocked its cell death effect. The differential effect of PDTC on cell viability correlates well with the inhibition of NF-kappaB activities. In addition, PDTC differentially activated microtubule-associated protein (MAP) kinases, such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), but not p38, depending on its dose, and the coaddition of glutathione (GSH), other antioxidants, and metal ions also modulated their activities. Furthermore, stable Bcl-2 expression blocked the PDTC-induced cell death. These results suggest that the thiol groups and free zinc and copper ion levels are important for the novel biphasic PDTC effect on cell viability, which is associated with the differential activation of NF-kappaB and MAP kinases. SN - 0360-4012 UR - https://www.unboundmedicine.com/medline/citation/10658192/Novel_biphasic_effect_of_pyrrolidine_dithiocarbamate_on_neuronal_cell_viability_is_mediated_by_the_differential_regulation_of_intracellular_zinc_and_copper_ion_levels_NF_kappaB_and_MAP_kinases_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0360-4012&date=2000&volume=59&issue=1&spage=117 DB - PRIME DP - Unbound Medicine ER -