QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:
Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF) All Versions of this Article: 10/3/309    most recent 15228517-2007-063v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yu, C. Articles by Adjei, A. A. Search for Related Content PubMed PubMed Citation Social Bookmarking                   What's this?

Mitochondrial Bax translocation partially mediates synergistic cytotoxicity between histone deacetylase inhibitors and proteasome inhibitors in glioma cells

Departments of Oncology (B.B.F.), Laboratory Medicine and Pathology (L.Y.), Thoracic Surgery (D.W.), and Radiation Oncology (J.S.), Mayo Clinic, Rochester, MN; Novartis Institutes for Biomedical Research (P.A.), Boston, MA; Department of Medicine, Roswell Park Cancer Institute (C.Y., A.A.A.), Buffalo, NY; USA

Address correspondence to Alex A. Adjei, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY USA 14263 (alex.adjei{at}roswellpark.org).

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.

Key Words: apoptosis • Bax • bortezomib (PS-341) • glioma • LBH589

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. Idbaih, F. Ducray, M. Sierra Del Rio, K. Hoang-Xuan, and J.-Y. Delattre Therapeutic Application of Noncytotoxic Molecular Targeted Therapy in Gliomas: Growth Factor Receptors and Angiogenesis Inhibitors Oncologist, September 1, 2008; 13(9): 978 - 992. [Abstract] [Full Text] [PDF]