gms | German Medical Science

59th Annual Meeting of the German Society of Neurosurgery (DGNC)
3rd Joint Meeting with the Italian Neurosurgical Society (SINch)

German Society of Neurosurgery (DGNC)

1 - 4 June 2008, Würzburg

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Sensitization of glioblastoma cells for treatment-induced apoptosis by PI3 kinase inhibition via modulation of DNA damage/repair

Sensitivierung von Glioblastomzellen für therapieinduzierte Apoptose durch Hemmung der PI3 Kinase via Modulation von DNA Reparaturmechanismen

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  • corresponding author J. Seidel - Neurochirurgische Klinik, Universität Ulm
  • M. Westhoff - Klinik für Kinder- und Jugendmedizin, Universität Ulm
  • G. Antoniadis - Neurochirurgische Klinik, Universität Ulm
  • V. Braun - Neurochirurgische Abteilung, Ev.Jung-Stilling-Krankenhaus Siegen
  • K. Debatin - Klinik für Kinder- und Jugendmedizin, Universität Ulm
  • S. Fulda - Klinik für Kinder- und Jugendmedizin, Universität Ulm

Deutsche Gesellschaft für Neurochirurgie. Società Italiana di Neurochirurgia. 59. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC), 3. Joint Meeting mit der Italienischen Gesellschaft für Neurochirurgie (SINch). Würzburg, 01.-04.06.2008. Düsseldorf: German Medical Science GMS Publishing House; 2008. DocP 008

The electronic version of this article is the complete one and can be found online at: http://www.egms.de/en/meetings/dgnc2008/08dgnc276.shtml

Published: May 30, 2008

© 2008 Seidel et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.

Outline

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Objective: Despite aggressive therapy patients with Glioblastoma multiforme have a poor prognosis. Deregulation of the PI3-Kinase (PI3K) survival pathway via different mechanisms has been reported in a significant proportion of glioblastoma tumor samples and correlates with poor prognosis. Therefore, modulation of the PI3-K pathway seems to be a promising approach to target therapy resistance of glioblastoma.

Methods: To reverse drug resistance we targeted PI3K by using a PI3K class I specific as well as a classical broad range PI3K family inhibitor. Glioblastoma cell lines (U87MG, U138MG and U118MG) as well as primary cultured cells isolated from patients with glioblastoma were used. While apoptosis was measured by FACs analysis of propidium iodide-stained nuclei, DNA damage/repair (yH2AX positivity and comet assay) were determined by fluorescence microscopy followed by computer analysis. For in vivo experiments U87MG cells were stereotactically implanted into the right striatum of CD1-nude mice.

Results: Inhibition of PI3K significantly sensitized glioblastoma cells for apoptosis by various anticancer drugs, such as temozolomide and the topoisomerase II inhibitors doxorubicin and etoposide in a time- and dose-dependent manner. Analysis of the underlying molecular mechanisms revealed a differential response in the cells´ DNA damage/repair pathways. In particular, the total number and duration of yH2AX-foci positive cells upon treatment with doxorubicin were increased by up to 20% in the presence of the PI3-K inhibitor. These findings were confirmed by detailed analysis of DNA damage by the comet assay, here an increase in damage of 38% (after 12hrs) and 54% (after 18hrs) was observed by combinatorial treatment. Furthermore, an orthotopic tumor model in mouse was established to investigate the in vivo relevance of our findings.

Conclusions: By demonstrating that PI3K inhibitors enhance treatment-induced apoptosis in glioblastoma cells by interfering with the cell´s DNA damage/repair response, our findings have important implications for novel strategies in glioblastoma treatment. PI3K inhibitors represent a promising new partner for combinatorial treatment in glioblastoma.