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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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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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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DOI: https://doi.org/10.1007/s10637-011-9680-y