gms | German Medical Science

58. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e. V. (DGNC)

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

26. bis 29.04.2007, Leipzig

JS-K, a glutathione S-transferase-activated nitric oxide donor with potent antineoplastic activity in malignant gliomas

JS-K, ein Glutathion S-Transferase aktivierter Stickstoffmonoxiddonor mit antineoplastischer Wirkung in malignen Gliomen

Meeting Abstract

Suche in Medline nach

  • corresponding author A. Weyerbrock - Abteilung Allgemeine Neurochirurgie, Universitätsklinikum Freiburg
  • B. Baumer - Abteilung Allgemeine Neurochirurgie, Universitätsklinikum Freiburg
  • A. Papazoglou - Abteilung Stereotaktische Neurochirurgie, Universitätsklinikum Freiburg

Deutsche Gesellschaft für Neurochirurgie. 58. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC). Leipzig, 26.-29.04.2007. Düsseldorf: German Medical Science GMS Publishing House; 2007. DocFR.09.07

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/dgnc2007/07dgnc128.shtml

Veröffentlicht: 11. April 2007

© 2007 Weyerbrock 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: Glutathione S-transferases (GSTs) play an important role in multidrug resistance and are upregulated in many tumors including malignant gliomas. Nitric oxide (NO) inhibits growth and induces apoptosis in a variety of cell lines. The diazeniumdiolate prodrug JS-K was designed to generate NO on enzymatic activation by GST targeting the NO effect selectively to GST-overexpressing tumor cells. The antiproliferative effect of JS-K is studied in human U87 glioma cells in vitro.

Methods: Human U87 cells were cultured in a standardized manner and then incubated with JS-K with 8 different doses between 1 and 50 µM for 24h. Cell viability was assessed by MTT assay after 24, 48 and 72 hours to evaluate the time course of the NO effects and the recovery potential of the cells. All experiments were repeated 4 times and done in triplicates. The data was analysed statistically using ANOVA and Student's Newman Keul test.

Results: Exposure of U87 cells to JS-K was highly cytotoxic and showed a linear dose-dependent effect. The IC50 was approximately 30 µM, 25 µM and 20 µM for a 24, 48 and 72 hour culture period, respectively. U87 cells continued to die even after removal of the drug from the culture, possibly by apoptosis induction. No recovery was observed when extending the culture period. A JS-K concentration as low as 1 µM was capable of inducing a significant growth arrest after 72 hours (p=0.03).

Conclusions: This is the first report that the diazeniumdiolate prodrug JS-K which is a potent anticancer drug in leukemia and some gastrointestinal tumors in vivo and in vitro has potent antiproliferative effects in U87 gliomas. Targeting NO release to tumor cells by engineering a prodrug which releases the compound upon cleavage by an enzyme overexpressed in these tumors (GST) might be a new strategy in cancer therapy.