Greater cell cycle inhibition and cytotoxicity induced by 2-deoxy-d-glucose in tumor cells treated under hypoxic vs aerobic conditions

Maher, Johnathan C.; Krishan, Awtar; Lampidis, Théodore J.

doi:10.1007/s00280-003-0724-7

Cited by 192 publications

(169 citation statements)

References 25 publications

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“…Based on this principle, we previously showed that 2-DG and other glycolytic inhibitors preferentially kill hypoxic as opposed to aerobic tumor cells (3 -6). However, cells growing under hypoxia were found to be more resistant to the toxic effects of this glycolytic inhibitor compared with cells in which oxidative phosphorylation has been either chemically or genetically blocked (5). This result suggested that HIF might be implicated in the mechanism of resistance to 2-DG because cells exposed to hypoxia express HIF, whereas in the latter two models where oxygen is present, HIF is not expressed (22).…”

Section: Discussionmentioning

confidence: 41%

“…Previously, we found that cells treated with oxidative phosphorylation inhibitors were more sensitive to the toxic effects of 2-DG compared with cells growing under hypoxia (5). A possible explanation for this increased resistance to 2-DG is that HIF is expressed under hypoxic conditions but not when cells are treated with blockers of oxidative phosphorylation in the presence of oxygen.…”

Section: Hif Expression Correlates With Reduced Sensitivity To 2-dg Imentioning

confidence: 99%

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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: Discussionmentioning

confidence: 41%

Section: Hif Expression Correlates With Reduced Sensitivity To 2-dg Imentioning

confidence: 99%

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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“…It has been known for decades that 2-DG, similar to glucose starvation, promotes cell cycle arrest and tumor cell death (Table 1). The effects of glucose deprivation and 2-DG are stronger under hypoxia than in normoxia, indicating that in the absence of oxygen, cells rely on anerobic glycolysis and thus become more dependent on glucose Maher et al, 2004). As tumors are frequently subjected to hypoxia, drugs that kill better under hypoxia are particularly interesting for tumor treatment.…”

Section: Glucose Deprivation and Antiglycolytics Induce Cell Cycle Armentioning

confidence: 99%

Sugar-free approaches to cancer cell killing

et al. 2010

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Tumors show an increased rate of glucose uptake and utilization. For this reason, glucose analogs are used to visualize tumors by the positron emission tomography technique, and inhibitors of glycolytic metabolism are being tested in clinical trials. Upregulation of glycolysis confers several advantages to tumor cells: it promotes tumor growth and has also been shown to interfere with cell death at multiple levels. Enforcement of glycolysis inhibits apoptosis induced by cytokine deprivation. Conversely, antiglycolytic agents enhance cell death induced by radio-and chemotherapy. Synergistic effects are likely due to regulation of the apoptotic machinery, as glucose regulates activation and levels of proapoptotic BH3-only proteins such as Bim, Bad, Puma and Noxa, as well as the antiapoptotic Bcl-2 family of proteins. Moreover, inhibition of glucose metabolism sensitizes cells to death ligands. Glucose deprivation and antiglycolytic drugs induce tumor cell death, which can proceed through necrosis or through mitochondrial or caspase-8-mediated apoptosis. We will discuss how oncogenic pathways involved in metabolic stress signaling, such as p53, AMPK (adenosine monophosphate-activated protein kinase) and Akt/mTOR (mammalian target of rapamycin), influence sensitivity to inhibition of glucose metabolism. Finally, we will analyze the rationale for the use of antiglycolytic inhibitors in the clinic, either as single agents or as a part of combination therapies.

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“…For instance, several glycolytic inhibitors that target key glycolytic enzymes have been tested for their anticancer activity in vitro and in vivo. [4][5][6][7][8] Such a metabolic intervention seems to produce encouraging results, at least in experimental model systems.…”

Section: Introductionmentioning

confidence: 99%

Synergistic effect of targeting mTOR by rapamycin and depleting ATP by inhibition of glycolysis in lymphoma and leukemia cells

Pélicano

Zhang

et al. 2005

Leukemia

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The mammalian target of rapamycin (mTOR) pathway plays important roles in regulating nutrient metabolism and promoting the growth and survival of cancer cells, which exhibit increased glycolysis for ATP generation. In this study, we tested the hypothesis that inhibition of the mTOR pathway and glycolysis would synergistically impact the energy metabolism in cancer cells and may serve as an effective therapeutic strategy to kill malignant cells. Using human lymphoma cells and leukemia cells, we demonstrated that the combination of rapamycin, an mTOR inhibitor, with a glycolytic inhibitor produced synergistic cytotoxic effect, as evidenced by apoptosis and cell growth inhibition assays. Mechanistic studies showed that inhibition of the mTOR pathway by rapamycin alone sufficiently suppressed the phosphorylation of the downstream molecules p70S6K and 4E-BP-1, but only caused a moderate cytostatic effect. Combination of mTOR inhibition and blockage of glycolysis synergistically suppressed glucose uptake and severely depleted cellular ATP pools, leading to significant enhancement of cell killing. In contrast, combination of rapamycin and ara-C did not increase cytotoxicity in vitro. Our findings suggest that targeting mTOR pathway in combination with inhibition of glycolysis may be an effective therapeutic strategy for hematological malignancies. This mechanismbased drug combination warrants further investigation in preclinical and clinical settings.

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Greater cell cycle inhibition and cytotoxicity induced by 2-deoxy-d-glucose in tumor cells treated under hypoxic vs aerobic conditions

Cited by 192 publications

References 25 publications

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

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

Sugar-free approaches to cancer cell killing

Synergistic effect of targeting mTOR by rapamycin and depleting ATP by inhibition of glycolysis in lymphoma and leukemia cells

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