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Cytotoxic and antiproliferative effects of thymoquinone on rat C6 glioma cells depend on oxidative stress

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Abstract

Thymoquinone (TQ) is a highly perspective chemotherapeutic agent against gliomas and glioblastomas because of its ability to cross the blood–brain barrier and its selective cytotoxicity for glioblastoma cells compared to primary astrocytes. Here, we tested the hypothesis that TQ-induced mild oxidative stress provokes C6 glioma cell apoptosis through redox-dependent alteration of MAPK proteins. We showed that low concentrations of TQ (20–50 μM) promoted cell-cycle arrest and induced hydrogen peroxide generation as a result of NADH-quinone oxidoreductase 1-catalyzed two-electron reduction of this quinone. Similarly, low concentrations of TQ efficiently conjugated intracellular GSH disturbing redox state of glioma cells and provoking mitochondrial dysfunction. We demonstrated that high concentrations of TQ (70–100 μM) induced reactive oxygen species generation due to its one-electron reduction. TQ provoked apoptosis in C6 glioma cells through mitochondrial potential dissipation and permeability transition pore opening. The identified TQ modes of action on C6 glioma cells open up the possibility of considering it as a promising agent to enhance the sensitivity of cancer cells to standard chemotherapeutic drugs.

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Acknowledgements

This study was supported by the research grant of the Belarusian Republican Foundation for Fundamental Research (M17M-092) and Belarusian Ministry of Education (the national program of scientific research number 20161385).

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Authors and Affiliations

  1. Department of Biophysics, Faculty of Physics, Belarusian State University, 4 Nezavisimosti ave., 220030, Minsk, Belarus

    N. G. Krylova & T. A. Kulahava

  2. Department of Radiation Chemistry and Pharmaceutical Technologies, Faculty of Chemistry, Belarusian State University, 14 Leningradskaya st., 220030, Minsk, Belarus

    M. S. Drobysh, G. N. Semenkova & O. I. Shadyro

  3. Institute of Biophysics and Cell Engineering of National Academy of Sciences of Belarus, 27 Academicheskaya st., 220072, Minsk, Belarus

    S. V. Pinchuk

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  1. N. G. Krylova
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Krylova, N.G., Drobysh, M.S., Semenkova, G.N. et al. Cytotoxic and antiproliferative effects of thymoquinone on rat C6 glioma cells depend on oxidative stress. Mol Cell Biochem 462, 195–206 (2019). https://doi.org/10.1007/s11010-019-03622-8

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