The glycolytic inhibitor 2-deoxy-D-glucose enhances the efficacy of etoposide in ehrlich ascites tumor bearing mice

Gupta, Seema; Mathur, Rohit; Dwarakanath, Bilikere S.

doi:10.4161/cbt.4.1.1381

Cited by 41 publications

(30 citation statements)

References 47 publications

(42 reference statements)

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“…33 In this study, therefore, we employed a non-toxic dose, 5 mM 2-DG, combined with equimolar glucose, which by itself is not toxic and has been shown, for example, to enhance the cytotoxicity of topoisomerase inhibitors. 34 The extent of death of 2-DG-treated panc-1 cells in our experiments was small and was similar to that observed in untreated controls (3% death), confirming that 2-DG alone, at least at the dosage employed here, does not affect panc-1 cell survival. We therefore used this non-toxic dose of 2-DG for all subsequent experiments.…”

Section: Resultssupporting

confidence: 85%

FTS and 2-DG induce pancreatic cancer cell death and tumor shrinkage in mice

2012

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The Ras inhibitor S-trans-trans farnesylthiosalicylic acid (FTS) inhibits active Ras, which controls cell proliferation, differentiation, survival, and metabolism. FTS also inhibits HIF1α expression in cancer cells, leading to an energy crisis. The synthetic glucose analog 2-deoxy-D-glucose (2-DG), which inhibits glycolysis, is selectively directed to tumor cells that exhibit increased glucose consumption. The 2-DG enters tumor cells, where it competes with glucose for glycolytic enzymes. In cancer models, as well as in human phase 1 trials, 2-DG inhibits tumor growth without toxicity. We postulated that under normoxic conditions, tumor cells treated with FTS would be more sensitive than normal cells to 2-DG. We show here that combined treatment with FTS and 2-DG inhibited cancer cell proliferation additively, yet induced apoptotic cell death synergistically both in vitro and in vivo. The induced apoptosis was inferred from QVD-OPH inhibition, an increase in cleaved caspase 3, and loss of survivin. FTS and 2-DG when combined, but not separately, also induced an increase in fibrosis of the tumor tissue, chronic inflammation, and tumor shrinkage. Overall, these results suggest a possible new treatment of pancreatic tumors by the combined administration of FTS and 2-DG, which together induce pancreatic tumor cell death and tumor shrinkage under non-toxic conditions.

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Section: Resultssupporting

confidence: 85%

FTS and 2-DG induce pancreatic cancer cell death and tumor shrinkage in mice

2012

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“…Unlike the MCF-7 model, no efficacy was seen with STX140 alone, further highlighting the benefit of combining the two agents. Although some studies do report weight loss in response to 2DG (Maschek et al, 2004), our data, in both models, concur with those of Gupta et al (2005), who reported no weight loss in response to 2DG.…”

Section: Effect Of Stx140 and 2dg In Vivosupporting

confidence: 88%

“…Several studies have shown the antitumour activity of 2DG alone in vitro and in vivo (Kaplan et al, 1990;Liu et al, 2001;Aft et al, 2002;Maschek et al, 2004;Gupta et al, 2005;Lampidis et al, 2006). However, very few clinical studies have tested 2DG as a singleagent therapy and the results of such studies have been disappointing (Landau et al, 1958;Kaplan et al, 1990).…”

mentioning

confidence: 99%

2-Methoxyoestradiol-3,17-O,O-bis-sulphamate and 2-deoxy-D-glucose in combination: a potential treatment for breast and prostate cancer

et al. 2008

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Drug combination therapy is a key strategy to improve treatment efficacy and survival of cancer patients. In this study the effects of combining 2-methoxyoestradiol-3,17-O,O-bis-sulphamate (STX140), a microtubule disruptor, with 2-deoxy-D-glucose (2DG) were assessed in MCF-7 (breast) and LNCaP (prostate) xenograft models in vivo. In mice bearing MCF-7 xenografts, daily p.o. administration of STX140 (5 mg kg À1 ) resulted in a 46% (Po0.05) reduction of tumour volume. However, the combination of STX140 (5 mg kg À1 p.o.) and 2DG (2 g kg À1 i.p.) reduced tumour volume by 76% (Po0.001). 2-Methoxyoestradiol-3,17-O,O-bissulphamate also reduced tumour vessel density. 2-Deoxy-D-glucose alone had no significant effect on tumour volume or vessel density. A similar benefit of the combination treatment was observed in the LNCaP prostate xenograft model. In vitro the degree of inhibition of cell proliferation by STX140 was unaffected by oxygen concentrations. In contrast, the inhibition of proliferation by 2DG was enhanced under hypoxia by 20 and 25% in MCF-7 and LNCaP cells, respectively. The combination of STX140 and 2DG in LNCaP cells under normoxia or hypoxia inhibited proliferation to a greater extent than either compound alone. These results suggest that the antiangiogenic and microtubule disruption activities of STX140 may make tumours more susceptible to inhibition of glycolysis by 2DG. This is the first study to show the benefit of combining a microtubule disruptor with 2DG in the two most common solid tumours.

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“…It is possible that cells treated with the other agents become heavily reliant on glycolysis and therefore become more sensitive to 2-DOG. Combining 2-DOG with adriamycin, paclitaxel or etoposide diminishes the size and proliferation of human osteosarcoma, xeno-transplanted MV522 lung carcinoma and Ehrlich hepatoma-bearing mice in comparison with tumors treated with 2-DOG or anticancer drugs, separately [88][89][90]. This increased sensitivity towards anticancer drugs induced by 2-DOG is attributed to the high glycolysis-dependence of the tumor for ATP supply and may result from increased demands for ATP made by the cell damaging agents.…”

Section: Hexosephosphate Isomerase (Hpi)mentioning

confidence: 85%

HIF-1α Modulates Energy Metabolism in Cancer Cells by Inducing Over-Expression of Specific Glycolytic Isoforms

Marín‐Hernández¹,

Gallardo‐Pérez²,

Ralph³

et al. 2009

MRMC

389

287

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To develop new and more efficient anti-cancer strategies it will be important to characterize the products of transcription factor activity essential for tumorigenesis. One such factor is hypoxia-inducible factor-1alpha (HIF-1alpha), a transcription factor induced by low oxygen conditions and found in high levels in malignant solid tumors, but not in normal tissues or slow-growing tumors. In fast-growing tumors, HIF-1alpha is involved in the activation of numerous cellular processes including resistance against apoptosis, over-expression of drug efflux membrane pumps, vascular remodeling and angiogenesis as well as metastasis. In cancer cells, HIF-1alpha induces over-expression and increased activity of several glycolytic protein isoforms that differ from those found in non-malignant cells, including transporters (GLUT1, GLUT3) and enzymes (HKI, HKII, PFK-L, ALD-A, ALD-C, PGK1, ENO-alpha, PYK-M2, LDH-A, PFKFB-3). The enhanced tumor glycolytic flux triggered by HIF-1alpha also involves changes in the kinetic patterns of expressed isoforms of key glycolytic enzymes. The HIF-1alpha induced isoforms provide cancer cells with reduced sensitivity to physiological inhibitors, lower affinity for products and higher catalytic capacity (Vmax(f)) in forward reactions because of marked over-expression compared to those isoforms expressed in normal tissues. Some of the HIF1alpha-induced glycolytic isoforms also participate in survival pathways, including transcriptional activation of H2B histone (by LDH-A), inhibition of apoptosis (by HKII) and promotion of cell migration (by ENO-alpha). HIF-1alpha action may also modulate mitochondrial function and oxygen consumption by inactivating the pyruvate dehydrogenase complex in some tumor types, or by modulating cytochrome c oxidase subunit 4 expression to increase oxidative phosphorylation in other cancer cell lines. In this review, the roles of HIF-1alpha and HIF1alpha-induced glycolytic enzymes are examined and it is concluded that targeting the HIF1alpha-induced glucose transporter and hexokinase, important to glycolytic flux control, might provide better therapeutic targets for inhibiting tumor growth and progression than targeting HIF1alpha itself.

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The glycolytic inhibitor 2-deoxy-D-glucose enhances the efficacy of etoposide in ehrlich ascites tumor bearing mice

Cited by 41 publications

References 47 publications

FTS and 2-DG induce pancreatic cancer cell death and tumor shrinkage in mice

FTS and 2-DG induce pancreatic cancer cell death and tumor shrinkage in mice

2-Methoxyoestradiol-3,17-O,O-bis-sulphamate and 2-deoxy-D-glucose in combination: a potential treatment for breast and prostate cancer

HIF-1α Modulates Energy Metabolism in Cancer Cells by Inducing Over-Expression of Specific Glycolytic Isoforms

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The glycolytic inhibitor 2-deoxy-D-glucose enhances the efficacy of etoposide in ehrlich ascites tumor bearing mice

Cited by 41 publications

References 47 publications

FTS and 2-DG induce pancreatic cancer cell death and tumor shrinkage in mice

FTS and 2-DG induce pancreatic cancer cell death and tumor shrinkage in mice

2-Methoxyoestradiol-3,17-O,O-bis-sulphamate and 2-deoxy-D-glucose in combination: a potential treatment for breast and prostate cancer

HIF-1&#945; Modulates Energy Metabolism in Cancer Cells by Inducing Over-Expression of Specific Glycolytic Isoforms

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HIF-1α Modulates Energy Metabolism in Cancer Cells by Inducing Over-Expression of Specific Glycolytic Isoforms