Document Detail


Synergistic activity of histone deacetylase and proteasome inhibition against pancreatic and hepatocellular cancer cell lines.
MedLine Citation:
PMID:  21508352     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AIM: To determine the phenotypic effects of belinostat (bel) and bortezomib (bor) against pancreatic cancer (PC) and hepatocellular cancer (HCC) cell lines.
MATERIALS AND METHODS: Antiproliferative effects were assessed using a sulforhodamine B assay. Synergy was evaluated using the Chou and Talalay method. Apoptosis was measured by caspase-3/-7 activity and PARP cleavage. Downstream effector proteins were detected via immunoblotting. Quantitative nuclear magnetic resonance (NMR)-based metabolomics analysis was performed.
RESULTS: There were single-agent antiproliferative effects against PC and HCC cell lines; the combination of bel and bor (bel+bor) had a synergistic effect. There was up to a 45-fold induction of apoptosis over the control. Post-treatment cell death was associated with p21 up-regulation, more pronounced with treatment with bel+bor. Treatment with bel+bor enhanced hyperacetylation of histone H3 over single-agent bel. A metabolic signature was established for treatments with bor and bel+bor.
CONCLUSION: The combination of bel+bor displayed significant antiproliferative activity against PC and HCC cell lines, with exhibiting synergistic antiproliferative and proapoptotic patterns even at suboptimal single-agent doses.
Authors:
J L Spratlin; T M Pitts; G N Kulikowski; M P Morelli; J J Tentler; N J Serkova; S G Eckhardt
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Anticancer research     Volume:  31     ISSN:  1791-7530     ISO Abbreviation:  Anticancer Res.     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-04-21     Completed Date:  2011-07-26     Revised Date:  2014-01-10    
Medline Journal Info:
Nlm Unique ID:  8102988     Medline TA:  Anticancer Res     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  1093-103     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Combined Chemotherapy Protocols
Apoptosis / drug effects
Boronic Acids / pharmacology*
Carcinoma, Hepatocellular / drug therapy*,  metabolism,  pathology
Caspase 3 / metabolism
Cell Line, Tumor
Drug Synergism
Histone Deacetylase Inhibitors / pharmacology*
Humans
Hydroxamic Acids / pharmacology*
Immunoblotting
Liver Neoplasms / drug therapy,  metabolism,  pathology
Magnetic Resonance Spectroscopy
Metabolomics
Pancreatic Neoplasms / drug therapy*,  metabolism,  pathology
Protease Inhibitors / pharmacology*
Proteasome Endopeptidase Complex / metabolism
Proteasome Inhibitors*
Pyrazines / pharmacology*
Sulfonamides
Grant Support
ID/Acronym/Agency:
P30 CA046934/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Boronic Acids; 0/Histone Deacetylase Inhibitors; 0/Hydroxamic Acids; 0/Protease Inhibitors; 0/Proteasome Inhibitors; 0/Pyrazines; 0/Sulfonamides; 0/belinostat; 0/bortezomib; EC 3.4.22.-/Caspase 3; EC 3.4.25.1/Proteasome Endopeptidase Complex
Comments/Corrections

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


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