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Higher rates of glucose usage generally correlate with poor prognosis in several types of malignant tumours. Experimental studies (both in vitro and in vivo) have shown that 2-deoxy-D-glucose (2-DG), a glucose analog and glycolytic inhibitor, enhances radiation-induced damage selectively in tumor cells while protecting normal cells, thereby suggesting that 2-DG can be used as a differential radiomodifier to improve the efficacy of radiotherapy. Clinical trials undertaken to study the feasibility, safety, and validity of this suggested approach will be described. Based on 2-DG-induced radiosensitization observed in primary organ cultures of cerebral glioma tissues, clinical trials were designed taking into consideration the radiobiology of gliomas and pharmacokinetics of 2-DG. Phase I/II clinical trials have unequivocally demonstrated that a combination of 2-DG (200-300 mg 2-DG per kg body weight orally administered after overnight fasting, 20 min before irradiation) with large weekly fractions (5 Gy/fraction) of low-LET radiotherapy is well tolerated without any acute toxicity or late radiation damage to the normal brain tissue. Nonserious transient side effects similar to hypoglycemia induced disturbances like restlessness, nausea, and vomiting were observed at the 2-DG doses used. Data from these trials involving more than 100 patients have clearly indicated a moderate increase in the survival, with a significant improvement in the quality of life with clinicopathological evidence of protection of normal brain tissue. A phase III multicentric trial to evaluate the efficacy of the combined treatment is in progress. Directions for future studies are discussed.

The tumor microenvironment (TME) is an ensemble of non-tumor cells comprising fibroblasts, cells of the immune system, and endothelial cells, besides various soluble secretory factors from all cellular components (including tumor cells). The TME forms a pro-tumorigenic cocoon around the tumor cells where reprogramming of the metabolism occurs in tumor and non-tumor cells that underlies the nature of interactions as well as competitions ensuring steady supply of nutrients and anapleoretic molecules for the tumor cells that fuels its growth even under hypoxic conditions. This metabolic reprogramming also plays a significant role in suppressing the immune attack on the tumor cells and in resistance to therapies. Thus, the metabolic cooperation and competition among the different TME components besides the inherent alterations in the tumor cells arising out of genetic as well as epigenetic changes supports growth, metastasis, and therapeutic resistance. This review focuses on the metabolic remodeling achieved through an active cooperation and competition among the three principal components of the TME—the tumor cells, the T cells, and the cancer-associated fibroblasts while discussing about the current strategies that target metabolism of TME components. Further, we will also consider the probable therapeutic opportunities targeting the various metabolic pathways as well as the signaling molecules/transcription factors regulating them for the development of novel treatment strategies for cancer.

Oral administration of 2-DG combined with large fractions of radiation (5 Gy/fraction/week) is safe and could be tolerated in glioblastoma patients without any acute toxicity and late radiation damage to the normal brain. Further clinical studies to evaluate the efficacy of the combined treatment are warranted.

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The glucose analog 2-deoxy-D-glucose (2-DG), an inhibitor of glucose transport and glycolytic ATP production, is the most widely investigated metabolic inhibitor for targeting glucose metabolism. Besides depleting energy in cells, 2-DG has also been found to alter N-linked glycosylation leading to unfolded protein responses and induce changes in gene expression and phosphorylation status of proteins involved in signaling, cell cycle control, DNA repair, calcium influx, and apoptosis. Inhibition of cell proliferation and induction of apoptosis have been observed as cytotoxic effects in a wide variety of tumor cells in vitro, while sensitization of tumor cells to ionizing radiation and certain chemotherapeutic drugs is associated with enhanced mitotic as well as apoptotic cell death induced by the primary therapeutic agent. Therefore, there has been a considerable amount of interest in developing 2-DG as a therapeutic agent or adjuvant in the radiotherapy and chemotherapy of tumors.