Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2-Deoxy-D-glucose (2DG), a well-known inhibitor of anaerobic glycolysis, is expected to exert cytotoxic and radiosensitizing effects. In order to test this hypothesis, the response of four tumor cell lines (U87-MG, GaMG, A549 and HT1080) to 2DG was analyzed for cell proliferation, changes in cell volume and nucleus size, as well as for radiation-induced DNA fragmentation, measured by the alkaline Comet assay. Two methods were used for loading cells with 2DG. The long-term method included cell cultivation in the presence of 5 mM 2DG for 24 h, while rapid intracellular delivery of 2DG was achieved by exposing the cells for 20 min to a hypotonic solution containing 100 mM 2DG. Irrespective of the loading method, 2DG inhibited the growth of HT1080 and A549 cells. In contrast, two glioblastoma lines (U87 and GaMG) were resistant to 2DG. In three of the four cell lines (all except HT1080), long-term treatment with 2DG reduced radiation-induced DNA fragmentation in conjunction with 2DG-mediated nucleus shrinkage (probably via chromatin condensation) in non-irradiated cells. Complementary volumetric experiments revealed the avid hypotonic uptake of 2DG by all tumor lines. Nonetheless, only HT1080 cells exhibited a significant increase in radiation-induced DNA fragmentation upon hypotonic loading with 2DG, associated with marked nucleus expansion in non-irradiated samples. Our data suggest that, dependant on cell type as well as on medium composition and tonicity, sugar treatment can induce the compaction or expansion of chromatin, thus decreasing or increasing radiation-induced DNA fragmentation. These results raise interesting questions for further studies on the mechanistic links between the sugar-modulated cell volume changes, chromatin structure and radiosensitivity of tumor and normal cells.
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PMID:Intracellular delivery of 2-deoxy-D-glucose into tumor cells by long-term cultivation and through swelling-activated pathways: implications for radiation treatment. 2147 78

Hypoxia is a characteristic of solid tumors especially Glioblastoma and is critical to chemoresistance. Cancer stem cells present in hypoxic niches are known to be a major cause of the progression, metastasis and relapse. We tried to identify synergistic combinations of drugs effective in both hypoxia and normoxia in tumor cells as well as in cancer stem cells. Since COX-2 is over-expressed in subset of glioblastoma and is also induced in hypoxia, we studied combinations of a prototype Cyclooxygenase (COX-2) inhibitor, NS-398 with various drugs (BCNU, Temozolomide, 2-Deoxy-D-glucose and Cisplatin) for their ability to abrogate chemoresistance under both severe hypoxia (0.2% O2) and normoxia (20% O2) in glioma cells. The only effective combination was of NS-398 and BCNU which showed a synergistic effect in both hypoxia and normoxia. This synergism was evident at sub-lethal doses for either of the single agent. The effectiveness of the combination resulted from increased pro- apoptotic and decreased anti-apoptotic molecules and increased caspase activity. PGE2 levels, a manifestation of COX-2 activity were increased during hypoxia, but were reduced by the combination during both hypoxia and normoxia. The combination reduced the levels of epithelial-mesenchymal transition (EMT) markers. It also resulted in a greater reduction of cell migration. While single drugs could reduce the number of gliomaspheres, the combination successfully abrogated their formation. The combination also resulted in a greater reduction of the cancer stem cell marker CD133. This combination could be a prototype of possible therapy in a tumor with a high degree of hypoxia like glioma.
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PMID:A drug combination targeting hypoxia induced chemoresistance and stemness in glioma cells. 2971 10