Document Detail


Dicoumarol enhances gemcitabine-induced cytotoxicity in high NQO1-expressing cholangiocarcinoma cells.
MedLine Citation:
PMID:  20480521     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Benjaporn Buranrat; Auemduan Prawan; Upa Kukongviriyapan; Sarinya Kongpetch; Veerapol Kukongviriyapan
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  World journal of gastroenterology : WJG     Volume:  16     ISSN:  1007-9327     ISO Abbreviation:  World J. Gastroenterol.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-18     Completed Date:  2010-08-26     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  100883448     Medline TA:  World J Gastroenterol     Country:  China    
Other Details:
Languages:  eng     Pagination:  2362-70     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
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MeSH Terms
Descriptor/Qualifier:
Antimetabolites, Antineoplastic / 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:
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; 66-76-2/Dicumarol; 70-18-8/Glutathione; 951-77-9/Deoxycytidine; B76N6SBZ8R/gemcitabine; EC 1.6.5.2/NAD(P)H Dehydrogenase (Quinone); EC 1.6.5.2/NQO1 protein, human
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