Mitochondrial Bax translocation partially mediates synergistic cytotoxicity between histone deacetylase inhibitors and proteasome inhibitors in glioma cells
Open Access
- 1 June 2008
- journal article
- Published by Oxford University Press (OUP) in Neuro-Oncology
- Vol. 10 (3), 309-319
- https://doi.org/10.1215/15228517-2007-063
Abstract
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.Keywords
This publication has 43 references indexed in Scilit:
- Aggresome induction by proteasome inhibitor bortezomib and α-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cellsBlood, 2006
- Anticancer activities of histone deacetylase inhibitorsNature Reviews Drug Discovery, 2006
- Histone Deacetylase Inhibitor Depsipeptide (FK228) Induces Apoptosis in Leukemic Cells by Facilitating Mitochondrial Translocation of Bax, Which Is Enhanced by the Proteasome Inhibitor BortezomibActa Haematologica, 2006
- Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancerNature Reviews Cancer, 2006
- Effect of trichostatin A, a histone deacetylase inhibitor, on glioma proliferation in vitro by inducing cell cycle arrest and apoptosisJournal of Neurosurgery: Pediatrics, 2005
- Synergistic apoptosis induction by proteasome and histone deacetylase inhibitors is dependent on protein synthesisApoptosis, 2005
- Suberoylanilide hydroxamic acid (SAHA) has potent anti‐glioma properties in vitro, ex vivo and in vivoJournal of Neurochemistry, 2005
- Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis in human glioblastoma multiforme (GBM)Oncogene, 2004
- Synergistic Effect of Histone Deacetylase Inhibitors FK228 and m-Carboxycinnamic Acid Bis-Hydroxamide with Proteasome Inhibitors PSI and PS-341 against Gastrointestinal Adenocarcinoma CellsClinical Cancer Research, 2004
- ×Phosphorylation of Bax Ser184 by Akt Regulates Its Activity and Apoptosis in NeutrophilsJournal of Biological Chemistry, 2004