Involvement of activating transcription factors JNK, NF-κB, and AP-1 in apoptosis induced by pyrrolidine dithiocarbamate/Cu complex
Journal
European Journal of Pharmacology
Journal Volume
594
Journal Issue
1-3
Pages
9-17
Date Issued
2008
Author(s)
Abstract
Pyrrolidine dithiocarbamate (PDTC) is a metal chelator. Biologically, slight toxic affects EC50, 100 ± 5.9?μM are observed when added to cultured HL-60 cells. CuCl2 at a physiological concentration (1?μM), but not FeCl2, Pb potentiated the cytotoxic effect of PDTC by 700 fold (EC50, 0.14 ± 0.02?μM). Furthermore, results indicated that the PDTC/Cu complex induced an apoptotic process, evidenced by apoptotic bodies, DNA ladder and hypodiploidy cells. Additional studies showed that PDTC/Cu complex significantly decreased mitochondrial membrane potential, increased cytochrome c release, and reactive oxygen species production, and depleted reduced non-protein thiols in a time-dependent manner. Following oxidative stress, the PDTC/Cu complex sequentially activated JNK, NF-κB and AP-1 signaling pathways while IκB kinase activity was enhanced. The apoptotic process was eventually induced by caspase 3 activation and PARP degradation. The non-permeable copper-specific chelator-bathocuproine disulfonate (BCPS) and vitamin C were able to inhibit apoptosis and the elevation of intracellular Cu. Based on these findings; we conclude that PDTC/Cu complex-induced apoptosis is mediated by activation of JNK, NF-κB, AP-1 and caspase 3. Due to its high potency, PDTC may be useful as a therapeutic anti-cancer drug. ? 2008.
Subjects
AP-1; Apoptosis; BCPS; Caspase; Copper; JNK; NF-κB; Oxidative stress; PDTC
SDGs
Other Subjects
ascorbic acid; bathocuproine disulfonate; chelating agent; copper; copper chloride; cytochrome c; I kappa B kinase; immunoglobulin enhancer binding protein; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; pyrrolidine dithiocarbamate; reactive oxygen metabolite; stress activated protein kinase; transcription factor AP 1; unclassified drug; apoptosis; article; cell culture; cell level; cell strain HL 60; concentration response; controlled study; culture medium; drug cytotoxicity; drug effect; drug mechanism; drug potency; enzyme activation; enzyme activity; enzyme degradation; enzyme release; human; human cell; mitochondrial membrane potential; priority journal; signal transduction; time; Apoptosis; Caspase 3; Cell Survival; Copper; Cytochromes c; DNA Fragmentation; Electrophoretic Mobility Shift Assay; Flow Cytometry; Free Radicals; HL-60 Cells; Humans; I-kappa B Kinase; JNK Mitogen-Activated Protein Kinases; Membrane Potentials; Mitochondrial Membranes; NF-kappa B; Poly(ADP-ribose) Polymerases; Pyrrolidines; Spectrophotometry, Atomic; Sulfhydryl Compounds; Thiocarbamates; Transcription Factor AP-1
Type
journal article