Document Detail

The cyclin-dependent kinase inhibitor flavopiridol sensitizes human hepatocellular carcinoma cells to TRAIL-induced apoptosis.
MedLine Citation:
PMID:  16820931     Owner:  NLM     Status:  MEDLINE    
Flavopiridol was one of the first cyclin-dependent kinase inhibitors demonstrated to have an antitumor effect in several cancer types. Here, we investigated the effects of flavopiridol on TNF-related apoptosis-inducing ligand (TRAIL) in the human hepatocellular carcinoma (HCC) cell lines HLE and HepG2, and evaluated the role of flavopiridol in apoptosis. To better understand the mechanism of increased TRAIL sensitivity in HCC cells, we determined the effect of flavopiridol on cell surface expression of TRAIL and TRAIL receptors using flow cytometry analysis. The levels of survivin, FLIP, Bcl-xL and X-chromosome-linked IAP (XIAP) in treated and untreated cells was also determined. Flavopiridol decreased cell viability in a dose-dependent manner in the two HCC cell lines tested. The pan-caspase inhibitor z-VAD-FMK did not inhibit the effect. However, subtoxic levels of flavopiridol dramatically enhanced TRAIL-induced apoptosis in both cells. Flavopiridol up-regulated TRAIL, TRAIL-R1 and TRAIL-R2 in both cell lines. In addition, flavopiridol down-regulated expression of survivin in both cell lines, and expression of FLIP and Bcl-xL were down-regulated in HLE cells. In summary, flavopiridol augmented TRAIL sensitivity by up-regulation of TRAIL receptors and down-regulation of survivin, FLIP and Bcl-xL. Thus, combining flavopiridol with a TRAIL agonist may prove to be an effective new strategy for treatment of HCC.
Kazumi Miyashita; Katsuya Shiraki; Hiroyuki Fuke; Tomoko Inoue; Yutaka Yamanaka; Yumi Yamaguchi; Norihiko Yamamoto; Keiichi Ito; Kazushi Sugimoto; Takeshi Nakano
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  International journal of molecular medicine     Volume:  18     ISSN:  1107-3756     ISO Abbreviation:  Int. J. Mol. Med.     Publication Date:  2006 Aug 
Date Detail:
Created Date:  2006-07-05     Completed Date:  2007-04-04     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9810955     Medline TA:  Int J Mol Med     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  249-56     Citation Subset:  IM    
First Department of Internal Medicine, Mie University School of Medicine, Tsu, Mie 514-8507, Japan.
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MeSH Terms
Antigens, CD95 / metabolism
Antineoplastic Agents / metabolism*
Apoptosis / physiology*
CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
Carcinoma, Hepatocellular / metabolism*
Cell Line, Tumor
Cell Survival
Cyclin-Dependent Kinases / antagonists & inhibitors*
Flavonoids / metabolism,  pharmacology*
Liver Neoplasms / metabolism*
Microtubule-Associated Proteins / metabolism
Neoplasm Proteins / metabolism
Piperidines / metabolism,  pharmacology*
Protein Kinase Inhibitors / metabolism
Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
TNF-Related Apoptosis-Inducing Ligand / metabolism*
Tumor Necrosis Factor-alpha / metabolism
bcl-X Protein / metabolism
Reg. No./Substance:
0/Antigens, CD95; 0/Antineoplastic Agents; 0/BCL2L1 protein, human; 0/BIRC5 protein, human; 0/CASP8 and FADD-Like Apoptosis Regulating Protein; 0/Flavonoids; 0/Microtubule-Associated Proteins; 0/Neoplasm Proteins; 0/Piperidines; 0/Protein Kinase Inhibitors; 0/Receptors, TNF-Related Apoptosis-Inducing Ligand; 0/TNF-Related Apoptosis-Inducing Ligand; 0/TNFSF10 protein, human; 0/Tumor Necrosis Factor-alpha; 0/bcl-X Protein; 146426-40-6/flavopiridol; EC Kinases

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