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Involvement of activating transcription factors JNK, NF-kappaB, and AP-1 in apoptosis induced by pyrrolidine dithiocarbamate/Cu complex.
Eur J Pharmacol. 2008 Oct 10; 594(1-3):9-17.EJ

Abstract

Pyrrolidine dithiocarbamate (PDTC) is a metal chelator. Biologically, slight toxic affects EC50, 100+/-5.9 microM are observed when added to cultured HL-60 cells. CuCl2 at a physiological concentration (1 microM), but not FeCl2, Pb potentiated the cytotoxic effect of PDTC by 700 fold (EC50, 0.14+/-0.02 microM). 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-kappaB and AP-1 signaling pathways while IkappaB 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-kappaB, AP-1 and caspase 3. Due to its high potency, PDTC may be useful as a therapeutic anti-cancer drug.

Authors+Show Affiliations

Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.No 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

18671963

Citation

Chen, Sung-Ho, et al. "Involvement of Activating Transcription Factors JNK, NF-kappaB, and AP-1 in Apoptosis Induced By Pyrrolidine dithiocarbamate/Cu Complex." European Journal of Pharmacology, vol. 594, no. 1-3, 2008, pp. 9-17.
Chen SH, Lin JK, Liang YC, et al. Involvement of activating transcription factors JNK, NF-kappaB, and AP-1 in apoptosis induced by pyrrolidine dithiocarbamate/Cu complex. Eur J Pharmacol. 2008;594(1-3):9-17.
Chen, S. H., Lin, J. K., Liang, Y. C., Pan, M. H., Liu, S. H., & Lin-Shiau, S. Y. (2008). Involvement of activating transcription factors JNK, NF-kappaB, and AP-1 in apoptosis induced by pyrrolidine dithiocarbamate/Cu complex. European Journal of Pharmacology, 594(1-3), 9-17. https://doi.org/10.1016/j.ejphar.2008.07.024
Chen SH, et al. Involvement of Activating Transcription Factors JNK, NF-kappaB, and AP-1 in Apoptosis Induced By Pyrrolidine dithiocarbamate/Cu Complex. Eur J Pharmacol. 2008 Oct 10;594(1-3):9-17. PubMed PMID: 18671963.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Involvement of activating transcription factors JNK, NF-kappaB, and AP-1 in apoptosis induced by pyrrolidine dithiocarbamate/Cu complex. AU - Chen,Sung-Ho, AU - Lin,Jen-Kun, AU - Liang,Yu-Chih, AU - Pan,Min-Hsiung, AU - Liu,Shing-Hwa, AU - Lin-Shiau,Shoei-Yn, Y1 - 2008/07/16/ PY - 2008/02/29/received PY - 2008/07/03/revised PY - 2008/07/10/accepted PY - 2008/8/2/pubmed PY - 2008/12/17/medline PY - 2008/8/2/entrez SP - 9 EP - 17 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 594 IS - 1-3 N2 - Pyrrolidine dithiocarbamate (PDTC) is a metal chelator. Biologically, slight toxic affects EC50, 100+/-5.9 microM are observed when added to cultured HL-60 cells. CuCl2 at a physiological concentration (1 microM), but not FeCl2, Pb potentiated the cytotoxic effect of PDTC by 700 fold (EC50, 0.14+/-0.02 microM). 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-kappaB and AP-1 signaling pathways while IkappaB 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-kappaB, AP-1 and caspase 3. Due to its high potency, PDTC may be useful as a therapeutic anti-cancer drug. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/18671963/Involvement_of_activating_transcription_factors_JNK_NF_kappaB_and_AP_1_in_apoptosis_induced_by_pyrrolidine_dithiocarbamate/Cu_complex_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(08)00765-6 DB - PRIME DP - Unbound Medicine ER -