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Enhancement of temozolomide-induced apoptosis by valproic acid in human glioma cell lines through redox regulation

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Abstract

Temozolomide (TMZ) is an oral alkylating agent that has been widely used in the treatment of refractory glioma, although inherent and acquired resistance to this drug is common. The clinical use of valproic acid (VPA) as an anticonvulsant and mood-stabilizing drug has been reported primarily for the treatment of epilepsy and bipolar disorder and less commonly for major depression. VPA is also used in the treatment of glioma-associated seizures with or without intracranial operation. In this study, we evaluated the potential synergistic effect of TMZ and VPA in human glioma cell lines. Compared with the use of TMZ or VPA alone, concurrent treatment with both drugs synergistically induced apoptosis in U87MG cells as evidenced by p53 and Bax expression, mitochondrial transmembrane potential loss, reactive oxygen species production, and glutathione depletion. This synergistic effect correlated with a decrease in nuclear translocation of the nuclear factor-erythroid 2 p45-related factor and corresponded with reduced heme oxygenase-1 and γ-glutamylcysteine synthetase expression. Pretreatment with N-acetylcysteine partially recovered the apoptotic effect of the TMZ/VPA combination treatment. The same degree of synergism is also seen in p53-mutant Hs683 cells, which indicates that p53 may not play a major role in the increased proapoptotic effect of the TMZ/VPA combination. In conclusion, VPA enhanced the apoptotic effect of TMZ, possibly through a redox regulation mechanism. The TMZ/VPA combination may be effective for treating glioma cancer and may be a powerful agent against malignant glioma. This drug combination should be further explored in the clinical setting.

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Acknowledgments

This work was supported by grant NSC 96-2320-B-415-002-MY3 (C.-H. Chen) from the National Science Council and grant CMRPG 660071 from the Chang Gung Medical Research Council, Taiwan, Republic of China.

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The authors report no potential conflict of interest relevant to this article.

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Authors and Affiliations

  1. Department of Neurosurgery, Chang Gung Memorial Hospital at Chiayi, College of Medicine, Chang Gung University, Tao-Yuan, 333, Taiwan

    Jen-Tsung Yang

  2. Department of Microbiology, Immunology and Biopharmaceuticals, College of Life Sciences, National Chiayi University, Chiayi City, 60004, Taiwan

    Ching-Hsein Chen

  3. Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, 110, Taiwan

    Yu-Jia Chang

  4. Department of Surgery, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan

    Yu-Jia Chang

  5. Institute of Agricultural Biotechnology, College of Agriculture, National Chiayi University, Chiayi, 60004, Taiwan

    Maurice S. B. Ku

  6. Department of Biology, The University of Memphis, Memphis, TN, 38152, USA

    King-Thom Chung

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  1. Ching-Hsein Chen
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  2. Yu-Jia Chang
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  3. Maurice S. B. Ku
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Correspondence to Jen-Tsung Yang.

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Chen, CH., Chang, YJ., Ku, M.S.B. et al. Enhancement of temozolomide-induced apoptosis by valproic acid in human glioma cell lines through redox regulation. J Mol Med 89, 303–315 (2011). https://doi.org/10.1007/s00109-010-0707-1

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  • DOI: https://doi.org/10.1007/s00109-010-0707-1

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