| Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells. | |
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MedLine Citation:
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PMID: 23033007 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Glioblastoma multiforme (GBM) cells are resistant to anticancer drugs. Cancer stem cells (CSCs) are a key mediator of chemoresistance. We have reported that disulfiram (DS), an aldehyde dehydrogenase (ALDH) inhibitor, targets breast CSC-like cells. In this study, the effect of DS and combination of DS and gemcitabine (dFdC) on GBM cells and GBM stem-like cells was investigated. METHODS: 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), combination index (CI)-isobologram, western blot, luciferase reporter gene assay, electrophoretic mobility-shift assay and ALDH analysis were used in this study. RESULTS: Disulfiram is cytotoxic in GBM cell lines in a copper (Cu)-dependent manner. Disulfiram/copper enhances the cytotoxicity of dFdC. Combination index-isobologram analysis indicates a synergistic effect between DS/Cu and dFdC. Disulfiram/copper induces reactive oxygen species (ROS), activates JNK and p38 pathways and inhibits nuclear factor-kappa B activity in GBM cell lines. Disulfiram/copper may trigger intrinsic apoptotic pathway via modulation of the Bcl2 family. Disulfiram/copper abolishes stem-like cell population in GBM cell lines. CONCLUSION: Our findings indicate that the cytotoxicity of DS/Cu and the enhancing effect of DS/Cu on the cytotoxicity of dFdC in GBM stem-like cells may be caused by induction of ROS and inhibition of both ALDH and the NFkB pathway. Both DS and dFdC can traverse the blood-brain barrier. Further study may lead them into GBM chemotherapy. |
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Authors:
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P Liu; S Brown; T Goktug; P Channathodiyil; V Kannappan; J-P Hugnot; P-O Guichet; X Bian; A L Armesilla; J L Darling; W Wang |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2012-10-02 |
Journal Detail:
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Title: British journal of cancer Volume: 107 ISSN: 1532-1827 ISO Abbreviation: Br. J. Cancer Publication Date: 2012 Oct |
Date Detail:
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Created Date: 2012-10-24 Completed Date: 2013-03-21 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 0370635 Medline TA: Br J Cancer Country: England |
Other Details:
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Languages: eng Pagination: 1488-97 Citation Subset: IM |
Affiliation:
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Research Institute in Healthcare Science, School of Applied Sciences, University of Wolverhampton, Wolverhampton, UK. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Aldehyde Dehydrogenase
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antagonists & inhibitors,
metabolism* Apoptosis / drug effects Brain Neoplasms / drug therapy*, enzymology, metabolism, pathology Cell Line, Tumor Copper / pharmacology* Cytotoxicity, Immunologic Deoxycytidine / analogs & derivatives, pharmacology Disulfiram / pharmacology* Drug Synergism Glioblastoma / drug therapy*, enzymology, metabolism, pathology Humans MAP Kinase Kinase 4 / metabolism MAP Kinase Signaling System / drug effects NF-kappa B / antagonists & inhibitors, metabolism Neoplastic Stem Cells / drug effects*, enzymology, pathology Reactive Oxygen Species / metabolism p38 Mitogen-Activated Protein Kinases / metabolism |
| Chemical | |
Reg. No./Substance:
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0/NF-kappa B; 0/Reactive Oxygen Species; 103882-84-4/gemcitabine; 7440-50-8/Copper; 951-77-9/Deoxycytidine; 97-77-8/Disulfiram; EC 1.2.1.3/Aldehyde Dehydrogenase; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; EC 2.7.12.2/MAP Kinase Kinase 4 |
| Comments/Corrections | |
Comment In:
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Br J Cancer. 2013 Mar 5;108(4):994
[PMID:
23340450
]
Br J Cancer. 2013 Mar 5;108(4):993 [PMID: 23340448 ] |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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