gms | German Medical Science

27. Deutscher Krebskongress

Deutsche Krebsgesellschaft e. V.

22. - 26.03.2006, Berlin

Increased cytotoxicity of ionizing radiation in combination with the membrane targeted apoptosis modulator erucylphosphocholine involves downregulation of PKB/Akt mediated survival signaling and induction of apoptosis

Meeting Abstract

  • corresponding author presenting/speaker René Handrick - Universitätsklinikum Tübingen, Klinik für Radioonkologie, Deutschland
  • Amelie Rübel - Universitätsklinikum Tübingen, Klinik für Radioonkologie
  • Hansjörg Eibl - Max-Planck-Institut für Biophysikalische Chemie, Göttingen
  • Claus Belka - Universitätsklinikum Tübingen, Klinik für Radioonkologie
  • Verena Jendrossek - Universitätsklinikum Tübingen, Klinik für Radioonkologie

27. Deutscher Krebskongress. Berlin, 22.-26.03.2006. Düsseldorf, Köln: German Medical Science; 2006. DocPO504

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/dkk2006/06dkk614.shtml

Veröffentlicht: 20. März 2006

© 2006 Handrick 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 vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Radiation therapy is an integral part of standard treatment concepts for patients suffering from glioblastoma multiforme. However, low intrinsic radiation sensitivity of the malignant cells constitutes a critical parameter for treatment failure. In this regard, aberrant apoptosis and survival signaling pathways acquired during tumor development constitute an attractive target for the modulation of the radiation response. Alkylphosphocholines, a novel class of antineoplastic agents, potently induce apoptosis of tumor cells without direct interaction with the DNA by targeting cellular membranes. We could recently show that the paradigmatic intravenously applicable derivative erucylphosphocholine (ErPC) efficiently induces growth arrest and apoptosis in human malignant glioma cell lines. Moreover, ErPC enhances cytotoxicity of ionizing radiation in vitro. Aim of the present study was to characterize molecular mechanisms of the combined action. Induction of apoptosis and necrosis in the human malignant glioma cell line T98G upon irradiation (1-10 Gy), treatment with ErPC (0-50µM) or combined therapy was determined by fluorescence microscopy. Cell cycle distribution was determined by flow cytometry. Caspase-activation and activity of PKB/Akt signaling and interacting pathways was verified by Western blot analysis using activation-specific antibodies. Treatment of T98G cells with ErPC strongly increased cytotoxicity of ionizing radiation. Analyzing the prevailing mechanism of cell death induction our data reveal that combined treatment with 10Gy induced higher levels apoptosis compared to necrosis at most drug-concentrations. On the molecular level, increased cytotoxicity of the combined treatment was accompanied by a more prominent cleavage of the effector caspase-substrate PARP, indicative for efficient caspase-activation and apoptosis. Moreover, combined treatment resulted in downregulation of PKB/Akt-mediated survival signaling. In this regard, treatment with ErPC alone or in combination with ionizing radiation strongly reduced activity of PKB/Akt and relevant downstream effectors and even counteracted irradiation-induced up-regulated activity of PKB/Akt. Our data suggest a role of caspase-activation and downregulation of PKB/Akt-mediated survival signaling in increased efficacy of the combination. The impact of defined downstream effectors of PKB/Akt in ErPC-mediated modulation of the radiation response is under current investigation.