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Cytotoxic effect of menadione and sodium orthovanadate in combination on human glioma cells

Investigational New Drugs volume 30, pages 1302–1310 (2012)Cite this article

Summary

Gliomas are the most common primary brain tumor, and their treatment is still a challenge. Here, we evaluated the antiproliferative effect of a novel combination of two potent oxidative stress enhancers: menadione (M) and sodium orthovanadate (SO). We observed both short-term and prolonged growth inhibitory effects of M or SO alone as well as in combination (M:SO) on DBTRG.05MG human glioma cells. A stronger antiproliferative effect was observed in the short-term proliferation assay with the M:SO combination compared to either investigated agent alone. In the long-term proliferation assay, a 10-day exposure to M:SO at concentrations of 10 μM:17.5 μM or 17.5 μM:10 μM was enough to kill 100% of the cells; no cell regrowth was observed after re-incubation in drug-free media. When used in combination, the single concentration of M and SO could be decreased by 2.5- to 5-fold of those used for each experimental drug alone and still obtain a similar antiproliferative effect. The underlying molecular mechanism was investigated by co-incubating M:SO with dithiothreitol (DTT) and genistein. Both substances partially neutralized the effects of the M:SO combination, showing additive effects. This observation suggests a role of oxidative stress and tyrosine kinase stimulation in the M:SO cytotoxic effect. Our results indicate that M:SO combination is an attractive alternative for glioma treatment that encourages further study. The neutralizing effects of genistein and DTT reveal a possibility for their use in the minimization of potential M:SO systemic toxicity.

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Acknowledgements

This study was supported by grants from the Swedish Research Council and the Karolinska Institute. We thank Dr Peter Siesjö for providing the patient-derived cells (hGCL10 - 12).

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Affiliations

  1. Department of Clinical Neuroscience R54, Karolinska Institute, Karolinska University Hospital, Huddinge, S-141 86, Stockholm, Sweden

    Zahid M. Delwar, Dimitrios Avramidis, Åke Siden, Mabel Cruz & Juan Sebastian Yakisich

  2. Immunology Section, Lund University, Lund, Sweden

    Elna Follin & Kajsa M. Paulsson

  3. Tianjin Huanhu Hospital, Tianjin, China

    Yan Hua

  4. Department of Neurology, Karolinska University Hospital, Stockholm, Sweden

    Åke Siden

  5. Department of Experimental Immunology, Institute of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark

    Kajsa M. Paulsson

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  1. Zahid M. Delwar
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  2. Dimitrios Avramidis
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  3. Elna Follin
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  4. Yan Hua
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Correspondence to Juan Sebastian Yakisich.

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Zahid M. Delwar and Dimitrios Avramidis contributed equally to this work.

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Delwar, Z.M., Avramidis, D., Follin, E. et al. Cytotoxic effect of menadione and sodium orthovanadate in combination on human glioma cells. Invest New Drugs 30, 1302–1310 (2012). https://doi.org/10.1007/s10637-011-9680-y

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Keywords

  • Gliomas
  • Menadione
  • Sodium orthovanadate
  • DTT
  • Genistein
  • Proliferation
  • Cytotoxicity