gms | German Medical Science

63. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Japanischen Gesellschaft für Neurochirurgie (JNS)

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

13. - 16. Juni 2012, Leipzig

Does the nitric oxide donor JS-K enhance sunitinib-mediated effects on brain tumor initiating cells in vitro?

Meeting Abstract

  • M. Schrödl - Neurochirurgische Universitätsklinik, Abteilung Allgemeine Neurochirurgie, Universitätsklinikum Freiburg; Klinik und Poliklinik für Neurologie, Universitätsklinikum Regensburg
  • N. Osterberg - Neurochirurgische Universitätsklinik, Abteilung Allgemeine Neurochirurgie, Universitätsklinikum Freiburg
  • P. Hau - Klinik und Poliklinik für Neurologie, Universitätsklinikum Regensburg
  • S. Möckel - Klinik und Poliklinik für Neurologie, Universitätsklinikum Regensburg
  • A.V. Vollmann-Zwerenz - Klinik und Poliklinik für Neurologie, Universitätsklinikum Regensburg
  • A. Weyerbrock - Neurochirurgische Universitätsklinik, Abteilung Allgemeine Neurochirurgie, Universitätsklinikum Freiburg

Deutsche Gesellschaft für Neurochirurgie. Japanische Gesellschaft für Neurochirurgie. 63. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Japanischen Gesellschaft für Neurochirurgie (JNS). Leipzig, 13.-16.06.2012. Düsseldorf: German Medical Science GMS Publishing House; 2012. DocFR.01.03

DOI: 10.3205/12dgnc167, URN: urn:nbn:de:0183-12dgnc1671

Veröffentlicht: 4. Juni 2012

© 2012 Schrödl 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

Objective: The dismal prognosis of glioblastoma multiforme (GBM) emphasizes the need for personalized multimodal treatment based on cellular, genetic and epigenetic characteristics. Experimental strategies include small-molecule, multitargeting tyrosine kinase inhibitors such as sunitinib and the exploration of synergisms between anticancer agents. Strong chemo- and radiosensitizing effects of nitric oxide (NO)-based tumor therapy were demonstrated in malignant gliomas. We hypothesize that the NO donor JS-K increases the sunitinib-mediated cytotoxic and antiproliferative effects in brain tumor initiating cells (BTIC) in vitro.

Methods: 3 primary GBM cell lines (LT, RAV19/21) were derived from surgical specimen and cultured under serum-free conditions. Stem cell-like gene expression was confirmed by immunocytochemistry for Nestin, Musashi, Sox2, O4 and CD133. O6-methylguanine methyltransferase (MGMT) promoter methylation status was assessed by methylation-specific PCR. Cells were treated with JS-K (0–25 μM) for 4 hours and/or sunitinib (0–100 μM) for 24 h. Cell viability was assessed 0–72 h after treatment by MTT assay. Inhibition of proliferation was assessed by colony formation assay. All experiments were performed in triplicate with 3 repetitions and analyzed by Student's unpaired t-test.

Results: Spheroid cultures of primary GBM cells exhibit an expression profile comparable to stem cells as they express Nestin, Musashi, Sox2 and O4. They do not express CD133, but exhibit clonogenic proliferation activity and have a heterogenic MGMT promoter methylation status. Here we show an inhibitory effect of sunitinib on proliferation and survival of BTIC. JS-K significantly reduces cell viability with an IC50 of 5 μM and decreases the proliferation capacity of primary GBM cells in a dose- and time-dependent manner. Concomitant treatment with sunitinib and JS-K increases the antitumor effect of each compound. Treatment efficacy of both sunitinib and JS-K is independent of the MGMT promoter methylation status.

Conclusions: The NO releasing prodrug JS-K exerts its strong antitumor effects in BTIC in a MGMT-independent manner and increases the cytotoxic and antiproliferative effects of sunitinib. Therefore, the combination of sunitinib and JS-K may be a novel experimental treatment concept in glioblastoma therapy offering the possibility to target different cell populations including BTIC within a tumor.