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D-amino acid oxidase gene therapy sensitizes glioma cells to the antiglycolytic effect of 3-bromopyruvate

Cancer Gene Therapy volume 19, pages 1–18 (2012)Cite this article

Abstract

Glioma tumors are refractory to conventional treatment. Glioblastoma multiforme is the most aggressive type of primary brain tumors in humans. In this study, we introduce oxidative stress-energy depletion (OSED) therapy as a new suggested treatment for glioblastoma. OSED utilizes D-amino acid oxidase (DAO), which is a promising therapeutic protein that induces oxidative stress and apoptosis through generating hydrogen peroxide (H2O2). OSED combines DAO with 3-bromopyruvate (3BP), a hexokinase II (HK II) inhibitor that interferes with Warburg effect, a metabolic alteration of most tumor cells that is characterized by enhanced aerobic glycolysis. Our data revealed that 3BP induced depletion of energetic capabilities of glioma cells. 3BP induced H2O2 production as a novel mechanism of its action. C6 glioma transfected with DAO and treated with D-serine together with 3BP-sensitized glioma cells to 3BP and decreased markedly proliferation, clonogenic power and viability in a three-dimensional tumor model with lesser effect on normal astrocytes. DAO gene therapy using atelocollagen as an in vivo transfection agent proved effective in a glioma tumor model in Sprague–Dawley (SD) rats, especially after combination with 3BP. OSED treatment was safe and tolerable in SD rats. OSED therapy may be a promising therapeutic modality for glioma.

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Acknowledgements

This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan. Cell lines used for this study were provided by BioResource room, The Institute for Enzyme Research, The University of Tokushima, Japan. We thank Y Okamura in Support Center for Advanced Medical Sciences, Institute of Health Biosciences, The University of Tokushima for assistance in flow cytometric analysis. We also appreciate Dr Young H Ko for her kind advice on 3BP dosage for in vivo study.

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Authors and Affiliations

  1. Division of Enzyme Pathophysiology, The Institute for Enzyme Research (KOSOKEN), The University of Tokushima, Kuramoto-cho, Tokushima, Japan

    S M El Sayed, R M Abou El-Magd, Y Shishido, S P Chung, T Sakai & K Fukui

  2. Department of Pediatrics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan

    S M El Sayed, H Watanabe & S Kagami

  3. Japan Science and Technology Agency, CREST, Kuramoto-cho, Tokushima, Japan

    K Fukui

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Correspondence to K Fukui.

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El Sayed, S., Abou El-Magd, R., Shishido, Y. et al. D-amino acid oxidase gene therapy sensitizes glioma cells to the antiglycolytic effect of 3-bromopyruvate. Cancer Gene Ther 19, 1–18 (2012). https://doi.org/10.1038/cgt.2011.59

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