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

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.