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Radiosensitization and Chemosensitization of Multicellular Tumor Spheroids by 2-Deoxy-d-Glucose is Stimulated by a Combination of TNFα and Glucose Deprivation-Induced Oxidative Stress

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Oxidative Stress in Cancer Biology and Therapy

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Abstract

Selective sensitization of tumor cells to radiation and chemotherapeutic drugs by the glycolytic inhibitor 2-deoxy-d-glucose (2-DG) arises from differential modifications of multiple damage response pathways in tumor and normal cells. Heterogeneity in responses to the combined treatment (2-DG + radiation/chemotherapeutic drugs) among mice bearing the same tumor has prompted studies on the roles of tumor physiology and host–tumor interactions. Using multicellular tumor spheroids (MTS), which mimic the microenvironment of tumors, we have addressed the issue of tumor physiology and found that the radio- and chemosensitization by 2-DG in MTS generated from a human glioma cell line (BMG-1) was nearly 2.5-fold higher than in monolayer cultures (MLCs), that correlated well with enhanced glycolysis in MTS. The enhanced sensitivity of MTS was accompanied by a profound induction of apoptotic and necrotic death as compared to cytogenetic damage-linked mitotic death as the major death pathway in MLC. Radio- and chemosensitization by 2-DG in MTS arose from endogenous TNFα-mediated oxidative stress and glucose deprivation-induced oxidative stress (due to the depletion of lactate) synergizing with oxidative stress induced by radiation and the chemotherapeutic drugs (like etoposide). Stimulation of MLC with TNFα elicited responses similar to MTS and supported its involvement in enhanced radio- and chemosensitization by 2-DG in MTS. Taken together, the available evidence suggests that alterations in cell signaling linked to tumor physiology, particularly related to endogenous and induced oxidative stress, contribute significantly to the radio- and chemosensitization of tumors by 2-DG.

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Acknowledgments

Research in author’s laboratory has been supported by grants (INM 280 and INM 301) from Defence Research and Development Organization (DRDO), the Government of India.

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Authors and Affiliations

  1. Division of Biocybernetics, Institute of Nuclear Medicine and Allied Sciences, Delhi, 110 054, India

    Divya Khaitan PhD & Bilikere S. Dwarakanath PhD

Authors
  1. Divya Khaitan PhD
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  2. Bilikere S. Dwarakanath PhD
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Corresponding author

Correspondence to Bilikere S. Dwarakanath PhD .

Editor information

Editors and Affiliations

  1. Free Radical & Radiation Biology, Graduate Program, University of Iowa, Iowa City, 52242, Iowa, USA

    Douglas R. Spitz

  2. Duluth Clinic, Radiation Oncology, University of Minnesota, East 3rd Street 400, Duluth, 55805, Minnesota, USA

    Kenneth J. Dornfeld

  3. James H. Quillen College of Medicine, Internal Medicine, East Tennessee State University, Johnson City, 37614, Tennessee, USA

    Koyamangalath Krishnan

  4. Radiation Oncology, Cancer Biology and Pediatrics, Vanderbilt Medical School, 21st Ave. 1161, Nashville, 37232, Tennessee, USA

    David Gius

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Khaitan, D., Dwarakanath, B.S. (2012). Radiosensitization and Chemosensitization of Multicellular Tumor Spheroids by 2-Deoxy-d-Glucose is Stimulated by a Combination of TNFα and Glucose Deprivation-Induced Oxidative Stress. In: Spitz, D., Dornfeld, K., Krishnan, K., Gius, D. (eds) Oxidative Stress in Cancer Biology and Therapy. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-397-4_5

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