Involvement of activating transcription factors JNK, NF-κB, and AP-1 in apoptosis induced by pyrrolidine dithiocarbamate/Cu complex

Sung Ho Chen, Jen Kun Lin, Yu Chih Liang, Min Hsiung Pan, Shing Hwa Liu, Shoei Yn Lin-Shiau

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)9-17
Number of pages9
JournalEuropean Journal of Pharmacology
Volume594
Issue number1-3
DOIs
Publication statusPublished - Oct 10 2008
Externally publishedYes

Keywords

  • AP-1
  • Apoptosis
  • BCPS
  • Caspase
  • Copper
  • JNK
  • NF-κB
  • Oxidative stress
  • PDTC

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

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