Document Detail


The growth inhibition of hepatocellular and cholangiocellular carcinoma cells by gemcitabine and the roles of extracellular signal-regulated and checkpoint kinases.
MedLine Citation:
PMID:  18813828     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We examined the effects of gemcitabine, a pyrimidine analogue, on hepatocellular carcinoma (HCC) and cholangiocellular carcinoma (CCC) cells. After HCC cells (HepG2, Hep3B, HLF and PLC/PRF/5) and CCC cells (HuCCT-1) were treated with gemcitabine, cellular growth, cell cycle, nuclear morphology and activity of signaling molecules were evaluated by WST-8 assays, flow cytometry analysis, Hoechst 33258 staining and Western blotting, respectively. We found that gemcitabine significantly inhibited the growth of HCC and CCC cells in a dose- and time-dependent manner. Gemcitabine induced cell cycle arrest at the G1 phase, however, the sub-G1 fraction was not observed and nuclear morphology did not indicate the induction of apoptosis. Gemcitabine induced differential activation of checkpoint kinases, Chk2 and Chk1, in HCC and CCC cells, respectively and gemcitabine activated extracellular signal-regulated kinase (ERK)1/2 in both cell types. After the cells were pretreated with a MEK inhibitor U0126, activations of these checkpoint kinases were abrogated and the cell death was enhanced. These results demonstrate that gemcitabine inhibited the growth of HCC and CCC cells by cell cycle arrest without apoptosis and that the ERK/Chk1/2 signaling pathway was in part responsible for the resistance to gemcitabine. Our findings shed light on treating patients with HCC and CCC by gemcitabine, especially when combined with a MEK inhibitor and Chk1/2 inhibitors.
Authors:
Kazuya Matsumoto; Takakazu Nagahara; Jun-Ichi Okano; Yoshikazu Murawaki
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Oncology reports     Volume:  20     ISSN:  1021-335X     ISO Abbreviation:  Oncol. Rep.     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-09-24     Completed Date:  2008-11-04     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  9422756     Medline TA:  Oncol Rep     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  863-72     Citation Subset:  IM    
Affiliation:
Second Department of Internal Medicine, Tottori University School of Medicine, Tottori, Japan.
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MeSH Terms
Descriptor/Qualifier:
Antimetabolites, Antineoplastic / pharmacology*
Apoptosis / drug effects
Bile Duct Neoplasms / drug therapy*,  pathology
Bile Ducts, Intrahepatic*
Carcinoma, Hepatocellular / drug therapy*,  pathology
Cell Cycle / drug effects
Cell Line, Tumor
Cholangiocarcinoma / drug therapy*,  pathology
Deoxycytidine / analogs & derivatives*,  pharmacology
Extracellular Signal-Regulated MAP Kinases / physiology*
Humans
Liver Neoplasms / drug therapy*,  pathology
Protein Kinases / physiology*
Protein-Serine-Threonine Kinases / physiology*
Chemical
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 951-77-9/Deoxycytidine; B76N6SBZ8R/gemcitabine; EC 2.7.-/Protein Kinases; EC 2.7.1.11/checkpoint kinase 2; EC 2.7.11.1/Checkpoint kinase 1; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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