gms | German Medical Science

55. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e. V. (DGNC)
1. Joint Meeting mit der Ungarischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

25. bis 28.04.2004, Köln

Reduction of glioma growth by treatment with inhibitors of histone deacetylases

Hemmung des Gliom-Wachstums durch Behandlung mit Inhibitoren der Histonen-Deacetylase

Meeting Abstract

  • corresponding author Ilker Eyüpoglu - Department of Neurosurgery, University of Erlangen-Nürnberg, Erlangen
  • E. Hahnen - Department of Neuropathology, University of Erlangen-Nürnberg, Erlangen
  • R. Buslei - Department of Neuropathology, University of Erlangen-Nürnberg, Erlangen
  • M. Lüders - Department of Medicine I, University of Erlangen-Nürnberg, Erlangen
  • I. Blümcke - Department of Neuropathology, University of Erlangen-Nürnberg, Erlangen
  • R. Fahlbusch - Department of Neurosurgery, University of Erlangen-Nürnberg, Erlangen

Deutsche Gesellschaft für Neurochirurgie. Ungarische Gesellschaft für Neurochirurgie. 55. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC), 1. Joint Meeting mit der Ungarischen Gesellschaft für Neurochirurgie. Köln, 25.-28.04.2004. Düsseldorf, Köln: German Medical Science; 2004. DocMO.12.05

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/dgnc2004/04dgnc0120.shtml

Veröffentlicht: 23. April 2004

© 2004 Eyüpoglu et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielf&aauml;ltigt, verbreitet und &oauml;ffentlich zug&aauml;nglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

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Objective

Malignant gliomas are known for their rapid growth and diffuse infiltration into adjacent brain parenchyma. In addition, glioma cells are commonly resistant to presently available adjuvant therapeutic strategies, such as radiation therapy and polychemotherapy. A novel class of pharmacological compounds called HDAC inhibitors are considered promising novel drugs for the treatment of cancer. The purpose of this study was to determine whether HDAC inhibitors are potent tools to block glioma growth.

Methods

8 different HDAC inhibitors (Apicidin, MS-275, VPA, TSA, CBHA, SBHA, SAHA, and M344) were analyzed for their potency to inhibit F98 glioma growth by using MTT assay. Cell cycle arrest and apoptosis were evaluated by FACS analysis. GFP transfected F98 glioma cells were transplanted onto hippocampal slice cultures to analyze glioma proliferation in an organotypic environment. To study AMPA receptor subunit expression RT-PCR and Western blotting were used. Finally, F98 glioma cells were transfected with cloned GluR1 subunit.

Results

Treatment of tumour cells with HDAC inhibitors cause significant reduction of glioma growth (about 60% compared to time-matched control) in F98 glioma single cell culture as well as after transplantation of GFP F98 cells onto organotypic hippocampal slice cultures. The treatment also resulted in a morphological alteration of glioma cells. By inhibiting the deacetylation of nucleosomal histones, the compounds cause chromatin remodeling that reverses aberrant transcriptional gene repression in tumours and leads to changes in gene expression inducing G0/G1 arrest, and/or apoptosis. G0/G1 arrest was achieved by Apicidin, MS-275, VPA, and SBHA. Finally, we were able to identify the AMPA receptor subunits as a potential target of HDAC inhibitors. We have analyzed a total of 10 different glioma cell lines with respect to their AMPA subunit expression pattern. Compared to primary astroglia used as control, none of the glioma cell lines expressed all four AMPA subunits. We characterized this restricted expression pattern as "common molecular phenotype" in glioma cells. Analysis of AMPA receptor subunit expression revealed that HDAC inhibitor treatment induced GluR1 re-expression in F98 cells, suggesting that GluR1 is epigenetically inactivated. Specific transfection of F98 cells with GluR1 also resulted in a dramatic growth reduction and morphological alteration.

Conclusions

HDAC inhibitors are considered as promising novel drugs for the treatment of cancer, including malignant gliomas. These data indicate that modulation of AMPA receptor subunit expression interferes with cell growth of malignant glioma in vitro and that the antiproliferative effect of HDAC inhibitors may partially result from re-expression of transcriptionally silenced GluR subunit genes.