Combination treatment based on metabolic effects of dinaline

Schaider, Helmut; Haberkorn, Uwe; Petru, Edgar; Berger, Martin R.

doi:10.1007/bf01366963

Cited by 1 publication

(1 citation statement)

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“…In fact, 2-DG treatment was found to significantly enhance the ability of both Adriamycin and cisplatin to reduce the tumor volume of human osteosarcoma and non -small cell lung cancer cells growing in nude mice (7). These data correlate with a previous study in which it was shown that 2-DG in combination with an experimental anticancer agent dinaline showed increased antitumor efficacy (8). Based on this background data, phase I clinical trials were initiated (February 2004) at the University of Miami Sylvester Cancer Center and San Antonio Cancer Center in Texas, using 2-DG to target the slow-growing hypoxic cells in combination with docetaxel, which attacks the rapidly dividing aerobic cells (protocol no.…”

Section: Introductionsupporting

confidence: 85%

Hypoxia-inducible factor-1 confers resistance to the glycolytic inhibitor 2-deoxy-d-glucose

Maher

Wangpaichitr

Savaraj

et al. 2007

Molecular Cancer Therapeutics

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Hypoxic regions within solid tumors harbor cells that are resistant to standard chemotherapy and radiotherapy. Because oxygen is required to produce ATP by oxidative phosphorylation, under hypoxia, cells rely more on glycolysis to generate ATP and are thereby sensitive to 2-deoxy-D-glucose (2-DG), an inhibitor of this pathway. Universally, cells respond to lowered oxygen tension by increasing the amount of glycolytic enzymes and glucose transporters via the well-characterized hypoxia-inducible factor-1 (HIF). To evaluate the effects of HIF on 2-DG sensitivity, the following three models were used: (a) cells treated with oligomycin to block mitochondrial function in the presence (HIF + ) or absence (HIF À ) of hypoxia, (b) cells treated with small interfering RNA specific for HIF-1A and control cells cultured under hypoxia, and (c) a mutant cell line unable to initiate the HIF response and its parental HIF + counterpart under hypoxic conditions. In all three models, HIF increased resistance to 2-DG and other glycolytic inhibitors but not to other chemotherapeutic agents. Additionally, HIF reduced the effects of 2-DG on glycolysis (as measured by ATP and lactate assays). Because HIF increases glycolytic enzymes, it follows that greater amounts of 2-DG would be required to inhibit glycolysis, thereby leading to increased resistance to it under hypoxia. Indeed, hexokinase, aldolase, and lactate dehydrogenase were found to be increased as a function of HIF under the hypoxic conditions and cell types we used; however, phosphoglucose isomerase was not. Although both hexokinase and phosphoglucose isomerase are known to interact with 2-DG, our findings of increased levels of hexokinase more likely implicate this enzyme in the mechanism of HIF-mediated resistance to 2-DG. Moreover, because 2-DG is now in phase I clinical trials, our results suggest that glycolytic inhibitors may be more effective clinically when combined with agents that inhibit HIF. [Mol Cancer Ther 2007;6(2):732 -41]

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Section: Introductionsupporting

confidence: 85%