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60th Annual Meeting of the German Society of Neurosurgery (DGNC)
Joint Meeting with the Benelux countries and Bulgaria

German Society of Neurosurgery (DGNC)

24 - 27 May 2009, Münster

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Inhibition of DNA damage repair by the Pyridinylfuranopyrimidine Inhibitor PI-103 sensitizes Glioblastoma cells for apoptosis

Meeting Abstract

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  • J. Kandenwein - Neurochirurgische Klinik, Universitätsklinikum Bonn
  • M.A. Westhoff - Kinderheilkunde, Klinikum der Universität Ulm
  • K.M. Deabtin - Kinderheilkunde, Klinikum der Universität Ulm
  • G. Antoniadis - Neurochirurgische Abteilung der Universität Ulm am BKH Günzburg
  • V. Braun - Neurochirurgische Abteilung, Ev.Jung-Stilling-Krankenhaus Siegen
  • S. Fulda - Kinderheilkunde, Klinikum der Universität Ulm

Deutsche Gesellschaft für Neurochirurgie. 60. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit den Benelux-Ländern und Bulgarien. Münster, 24.-27.05.2009. Düsseldorf: German Medical Science GMS Publishing House; 2009. DocMI.05-06

doi: 10.3205/09dgnc197, urn:nbn:de:0183-09dgnc1971

Published: May 20, 2009

© 2009 Kandenwein 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: Glioblastoma multiforme (GBM) are the most common primary brain tumors and among the deadliest cancers per se. The failure of conventional therapeutic approaches is – at least in part – believed to be due to aberrant activity of the PI3-Kinase/Akt initiated survival cascade, which can also lead to mTOR and DNA-PK mediated apoptosis resistance.

Methods: In this study we examine the effect of the novel Pyridinylfurano-pyrimidine Inhibitor PI-103, which blocks signalling mediated by PI3-Kinase and related kinases, in combination with inducers of the intrinsic apoptosis pathway (specifically: Etoposide, Doxorubicin and Temozolomide). Glioblastoma cell lines (U87MG, U138MG and U118MG) as well as primary cultured cells isolated from patients with glioblastoma were used.

Results: A significant sensitization effect for chemotherapeutic-induced cell death could be achieved by a combination treatment: In the presence of PI-103 all tested components increased their apoptotic potential to varying degrees. Importantly, this holds true not only in established GBM cell lines, but was also observed in primary cultured patients’ material. PI-103 enhanced the killing potential of these components by blocking signaling through the DNA-PK-mediated DNA repair mechanism. Indeed, pharmacological or genetic inhibition of PI3-Kinase (either by PI-103 or RNAi) and DNA-PK (either by Nu7026 or RNAi) led to similar levels of sensitization. No further argumentation could be observed by combining the inhibition of PI3-Kinase and DNA-PK, indicating that those two proteins exist in a linear relationship within this signalling cascade. In contrast, no sensitization for Doxorubicin-induced apoptosis was seen using pharmacological or genetic inhibition of mTOR.

Conclusions: Our findings are the first to show that the inhibition of PI3-Kinase mediated signalling combined with chemotherapeutic drugs sensitizes GBM cells for apoptosis. This clearly shows the potential of PI-103 in combination therapy for the treatment of GBM patients and suggests that the inhibitors ability to block PI3-Kinase and DNA-PK, the latter possibly indirectly, in contrast to the inhibition of mTOR, are important features which warrant further development.