Document Detail


Mitochondrial Bax translocation partially mediates synergistic cytotoxicity between histone deacetylase inhibitors and proteasome inhibitors in glioma cells.
MedLine Citation:
PMID:  18445700     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The effects of combining histone deacetylase (HDAC) inhibitors and proteasome inhibitors were evaluated in both established glioblastoma multiforme (GBM) cell lines and short-term cultures derived from the Mayo Clinic xenograft GBM panel. Coexposure of LBH589 and bortezomib at minimally toxic doses of either drug alone resulted in a striking induction of apoptosis in established U251, U87, and D37 GBM cell lines, as well as in GBM8, GBM10, GBM12, GBM14, and GBM56 short-term cultured cell lines. Synergism of apoptosis induction was also observed in U251 cells when coexposing cells to other HDAC inhibitors, including LAQ824 and trichostatin A, with the proteasome inhibitor MG132, thus demonstrating a class effect. In U251 cells, bortezomib alone or in combination with LBH589 decreased Raf-1 levels and suppressed Akt and Erk activation. LBH589 or bortezomib alone increased expression of the cell cycle regulators p21 and p27. Additionally, the combination, but not the individual agents, markedly enhanced JNK activation. Synergistic induction of apoptosis after exposure to LBH589 and bortezomib was partially mediated by Bax translocation from the cytosol to the mitochondria resulting from Bax conformational changes. Bax translocation precedes cytochrome c release and apoptosis, and selective down-regulation of Bax using siRNA significantly mitigates the cytotoxicity of LBH589 and bortezomib. This combination regimen warrants further preclinical and possible clinical study for glioma patients.
Authors:
Chunrong Yu; Bret B Friday; Lin Yang; Peter Atadja; Dennis Wigle; Jann Sarkaria; Alex A Adjei
Publication Detail:
Type:  Journal Article     Date:  2008-04-29
Journal Detail:
Title:  Neuro-oncology     Volume:  10     ISSN:  1522-8517     ISO Abbreviation:  Neuro-oncology     Publication Date:  2008 Jun 
Date Detail:
Created Date:  2008-07-23     Completed Date:  2008-08-26     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  100887420     Medline TA:  Neuro Oncol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  309-19     Citation Subset:  IM    
Affiliation:
Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Apoptosis / drug effects
Blotting, Western
Boronic Acids / administration & dosage
Brain Neoplasms / drug therapy*
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Synergism
Electrophoresis, Polyacrylamide Gel
Enzyme Inhibitors / administration & dosage*
Glioma / drug therapy*
Histone Deacetylase Inhibitors
Humans
Hydroxamic Acids / administration & dosage
Mitochondria / metabolism*
Proteasome Endopeptidase Complex / antagonists & inhibitors
Protein Transport / drug effects
Pyrazines / administration & dosage
RNA, Small Interfering
bcl-2-Associated X Protein / drug effects,  metabolism*
Chemical
Reg. No./Substance:
0/Boronic Acids; 0/Enzyme Inhibitors; 0/Histone Deacetylase Inhibitors; 0/Hydroxamic Acids; 0/LAQ824; 0/LBH589; 0/Pyrazines; 0/RNA, Small Interfering; 0/bcl-2-Associated X Protein; 0/bortezomib; 58880-19-6/trichostatin A; EC 3.4.25.1/Proteasome Endopeptidase Complex
Comments/Corrections

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