Document Detail


Sorafenib and HDAC inhibitors synergize to kill CNS tumor cells.
MedLine Citation:
PMID:  22406992     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The present studies were designed to determine whether the multi-kinase inhibitor sorafenib (Nexavar) interacted with histone deacetylase inhibitors to kill glioblastoma and medulloblastoma cells. In a dose-dependent fashion sorafenib lethality was enhanced in multiple genetically disparate primary human glioblastoma isolates by the HDAC inhibitor sodium valproate (Depakote). Drug exposure reduced phosphorylation of p70 S6K and of mTOR. Similar data to that with valproate were also obtained using the HDAC inhibitor vorinostat (Zolinza). Sorafenib and valproate also interacted to kill medulloblastoma and PNET cell lines. Treatment with sorafenib and HDAC inhibitors radio-sensitized both GBM and medulloblastoma cell lines. Knock down of death receptor (CD95) expression protected GBM cells from the drug combination, as did overexpression of c-FLIP-s, BCL-XL and dominant negative caspase 9. Knock down of PDGFRα recapitulated the effect of sorafenib in combination with HDAC inhibitors. Collectively, our data demonstrate that the combination of sorafenib and HDAC inhibitors kills through activation of the extrinsic pathway, and could represent a useful approach to treat CNS-derived tumors.
Authors:
Yong Tang; Adly Yacoub; Hossein A Hamed; Andrew Poklepovic; Gary Tye; Steven Grant; Paul Dent
Publication Detail:
Type:  Journal Article     Date:  2012-05-01
Journal Detail:
Title:  Cancer biology & therapy     Volume:  13     ISSN:  1555-8576     ISO Abbreviation:  Cancer Biol. Ther.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-07-19     Completed Date:  2012-12-14     Revised Date:  2013-11-18    
Medline Journal Info:
Nlm Unique ID:  101137842     Medline TA:  Cancer Biol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  567-74     Citation Subset:  IM    
Affiliation:
Department of Neurosurgery, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
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MeSH Terms
Descriptor/Qualifier:
Antigens, CD95 / genetics,  metabolism
Antineoplastic Agents / pharmacology*
Benzenesulfonates / pharmacology*
Cell Line, Tumor
Cell Survival / drug effects,  genetics
Central Nervous System Neoplasms / enzymology*,  genetics
Drug Synergism
Histone Deacetylase Inhibitors / pharmacology*
Humans
Protein Kinase Inhibitors / pharmacology
Pyridines / pharmacology*
Grant Support
ID/Acronym/Agency:
R01 CA141703/CA/NCI NIH HHS; R01 CA150214/CA/NCI NIH HHS; R01 DK052825/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, CD95; 0/Antineoplastic Agents; 0/Benzenesulfonates; 0/Histone Deacetylase Inhibitors; 0/Protein Kinase Inhibitors; 0/Pyridines; 0/sorafenib
Comments/Corrections

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


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