| Dicoumarol enhances gemcitabine-induced cytotoxicity in high NQO1-expressing cholangiocarcinoma cells. | |
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MedLine Citation:
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PMID: 20480521 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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AIM: To investigate whether dicoumarol, a potent inhibitor of NAD(P)H quinone oxidoreductase-1 (NQO1), potentiates gemcitabine to induce cytotoxicity in cholangiocarcinoma cells (CCA) and the role of reactive oxygen generation in sensitizing the cells. METHODS: Four human cell lines with different NQO1 activity were used; the human CCA cell lines, KKU-100, KKU-OCA17, KKU-M214, and Chang liver cells. NQO1 activity and mRNA expression were determined. The cells were pretreated with dicoumarol at relevant concentrations before treatment with gemcitabine. Cytotoxicity was determined by staining with fluorescent dyes. Oxidant formation was examined by assay of cellular glutathione levels and reactive oxygen species production by using dihydrofluorescein diacetate. Measurement of mitochondrial transmembrane potential was performed by using JC-1 fluorescent probe. Western blotting analysis was performed to determine levels of survival related proteins. RESULTS: Dicoumarol markedly enhanced the cytotoxicity of gemcitabine in KKU-100 and KKU-OCA17, the high NQO1 activity and mRNA expressing cells, but not in the other cells with low NQO1 activity. Dicoumarol induced a marked decrease in cellular redox of glutathione in KKU-100 cells, in contrast to KKU-M214 cells. Dicoumarol at concentrations that inhibited NQO1 activity did not alter mitochondrial transmembrane potential and production of reactive oxygen species. Gemcitabine alone induced activation of NF-kappaB and Bcl-(XL) protein expression. However, gemcitabine and dicoumarol combination induced increased p53 and decreased Bcl-(XL) levels in KKU-100, but not in KKU-M214 cells. CONCLUSION: NQO1 may be important in sensitizing cells to anticancer drugs and inhibition of NQO1 may be a strategy for the treatment of CCA. |
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Authors:
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Benjaporn Buranrat; Auemduan Prawan; Upa Kukongviriyapan; Sarinya Kongpetch; Veerapol Kukongviriyapan |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: World journal of gastroenterology : WJG Volume: 16 ISSN: 1007-9327 ISO Abbreviation: World J. Gastroenterol. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-05-18 Completed Date: 2010-08-26 Revised Date: 2012-05-28 |
Medline Journal Info:
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Nlm Unique ID: 100883448 Medline TA: World J Gastroenterol Country: China |
Other Details:
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Languages: eng Pagination: 2362-70 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antimetabolites, Antineoplastic
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pharmacology Antineoplastic Combined Chemotherapy Protocols / pharmacology* Bile Duct Neoplasms / enzymology*, genetics, pathology Bile Ducts, Intrahepatic / drug effects*, enzymology, pathology Cell Line, Tumor Cell Survival / drug effects Cholangiocarcinoma / enzymology*, genetics, pathology Deoxycytidine / analogs & derivatives, pharmacology Dicumarol / pharmacology Dose-Response Relationship, Drug Drug Resistance, Neoplasm Enzyme Inhibitors / pharmacology Glutathione / metabolism Humans Membrane Potential, Mitochondrial / drug effects NAD(P)H Dehydrogenase (Quinone) / antagonists & inhibitors*, genetics, metabolism NF-kappa B / metabolism Oxidation-Reduction Oxidative Stress / drug effects RNA, Messenger / metabolism Reactive Oxygen Species / metabolism Tumor Suppressor Protein p53 / metabolism bcl-X Protein / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Antimetabolites, Antineoplastic; 0/BCL2L1 protein, human; 0/Enzyme Inhibitors; 0/NF-kappa B; 0/RNA, Messenger; 0/Reactive Oxygen Species; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; 0/bcl-X Protein; 103882-84-4/gemcitabine; 66-76-2/Dicumarol; 70-18-8/Glutathione; 951-77-9/Deoxycytidine; EC 1.6.5.2/NAD(P)H Dehydrogenase (Quinone); EC 1.6.5.2/NQO1 protein, human |
| Comments/Corrections | |
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