2-Deoxy-d-glucose causes cytotoxicity, oxidative stress, and radiosensitization in pancreatic cancer

Coleman, Mitchell C.; Asbury, Carla; Daniels, David H.; Du, Juan; Aykin-Burns, Nūkhet; Smith, Brian J.; Li, Ling; Spitz, Douglas R.; Cullen, Joseph J.

doi:10.1016/j.freeradbiomed.2007.08.032

Cited by 134 publications

(105 citation statements)

References 23 publications

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“…A stronger 2-DG phenotype in the G6PD mutant would also be expected, if reduced activity of the PPP would contribute to the cytotoxicity of 2-DG (as suggested in ref. 16).…”

Section: Resultsmentioning

confidence: 99%

A catabolic block does not sufficiently explain how 2-deoxy-d-glucose inhibits cell growth

Ralser

Wamelink

Struys

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

144

156

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The glucose analogue 2-deoxy-D-glucose (2-DG) restrains growth of normal and malignant cells, prolongs the lifespan of C. elegans, and is widely used as a glycolytic inhibitor to study metabolic activity with regard to cancer, neurodegeneration, calorie restriction, and aging. Here, we report that separating glycolysis and the pentose phosphate pathway highly increases cellular tolerance to 2-DG. This finding indicates that 2-DG does not block cell growth solely by preventing glucose catabolism. In addition, 2-DG provoked similar concentration changes of sugar-phosphate intermediates in wild-type and 2-DG-resistant yeast strains and in human primary fibroblasts. Finally, a genome-wide analysis revealed 19 2-DG-resistant yeast knockouts of genes implicated in carbohydrate metabolism and mitochondrial homeostasis, as well as ribosome biogenesis, mRNA decay, transcriptional regulation, and cell cycle. Thus, processes beyond the metabolic block are essential for the biological properties of 2-DG.cell growth inhibition ͉ glycolysis ͉ off-target effect ͉ pentose phosphate pathway ͉ carbohydrate metabolism 2 -Deoxy-D-glucose (2-DG) is a stable glucose analogue that is actively taken up by the hexose transporters and phosphor ylated but cannot be fully metabolized. 2-DG-6-phosphate accumulates in the cell and interferes with carbohydrate metabolism by inhibiting glycolytic enzymes. 2-DG-6-phosphate inhibits phosphoglucose isomerase (PGI) in a competitive, and hexokinase (HXK) in a noncompetitive, manner (1-3). On the cellular level, 2-DG provokes rapid growth inhibition and results in altered glycosylation that is highly dependent on catabolic glucose intermediates (4, 5).2-DG has been used in numerous studies focused on the effects of reduced metabolic rates. Recently, 2-DG has been used in this study of glycolytic inhibition with respect to calorie restriction and aging. 2-DG increases the lifespan of C. elegans, an effect that is reversed by antioxidants (6, 7). Moreover, 2-DG mitigates disease progression in a murine model of temporal lobe epilepsy (8), possibly due to the repression of the BDNF promoter. 2-DG shows possibilities as an antiviral drug, as it targets gene expression in papillomavirus (9). Finally, 2-DG has been thoroughly studied in regard to cancer biology. Malignant cells exhibit increased glucose metabolism compared with surrounding tissue (10) and, therefore, increased 2-DG uptake. 2-DG efficiently inhibits tumor progression and is a focus of clinical trials (reviewed in ref. 11).In general, it is assumed that the biological effects of 2-DG are the consequence of a block in carbohydrate catalysis, implying that 2-DG treated cells, unable to metabolize glucose, stop growing as a result of a lack of energy and metabolic intermediates. However, several observations bring this assumption into question. First, only a moderate decline in ATP has been observed in 2-DG-treated eukaryotes (7,12). Second, a current study reveals that tumor cells react differently to 2-DG than to its close analogue 2-fluorod...

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“…A stronger 2-DG phenotype in the G6PD mutant would also be expected, if reduced activity of the PPP would contribute to the cytotoxicity of 2-DG (as suggested in ref. 16).…”

Section: Resultsmentioning

confidence: 99%

A catabolic block does not sufficiently explain how 2-deoxy-d-glucose inhibits cell growth

Ralser

Wamelink

Struys

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

144

156

View full text Add to dashboard Cite

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“…2DG inhibits the processing of glucose for both glycolysis and oxidative phosphorylation. Tumor cells are more sensitive to 2DG because they primarily use glycolysis for ATP generation and must increase glucose uptake to compensate for the lower yield of ATP per glucose molecule (23). KSHVinfected TIME cells have slightly higher basal-cell death levels 48 h postinfection than their mock-infected counterparts (Fig.…”

Section: Kshv Infection Decreases Mitochondrial Oxidative Phosphorylamentioning

confidence: 98%

“…Glycolytic inhibitors have been used to selectively eliminate cancer cells because of their requirement for high levels of glucose (20,21,23,24). These inhibitors have small effects on normal differentiated cells that predominantly use oxidative phosphorylation but quickly kill cancer cells.…”

Section: Kshv Infection Decreases Mitochondrial Oxidative Phosphorylamentioning

confidence: 99%

Induction of the Warburg effect by Kaposi's sarcoma herpesvirus is required for the maintenance of latently infected endothelial cells

Delgado

Carroll

Punjabi

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

201

218

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Kaposi's sarcoma (KS) is the most commonly reported tumor in parts of Africa and is the most common tumor of AIDS patients worldwide. KS-associated herpesvirus (KSHV) is the etiologic agent of KS. Although KS tumors contain many cell types, the predominant cell is the spindle cell, a cell of endothelial origin that maintains KSHV latency. KSHV activates many cell-signaling pathways but little is known about how KSHV alters cellular metabolism during latency. The Warburg effect, a common metabolic alteration of most tumor cells, is defined by an increase in aerobic glycolysis and a decrease in oxidative phosphorylation as an energy source. The Warburg effect adapts cells to tumor environments and is necessary for the survival of tumor cells. During latent infection of endothelial cells, KSHV induces aerobic glycolysis and lactic acid production while decreasing oxygen consumption, thereby inducing the Warburg effect. Inhibitors of glycolysis selectively induce apoptosis in KSHV-infected endothelial cells but not their uninfected counterparts. Therefore, similar to cancer cells, the Warburg effect is necessary for maintaining KSHV latently infected cells. We propose that KSHV induction of the Warburg effect adapts infected cells to tumor microenvironments, aiding the seeding of KS tumors. Additionally, inhibitors of glycolysis may provide a unique treatment strategy for latent KSHV infection and ultimately KS tumors.human herpesvirus-8 | gamma-herpesvirus | latency | glycolysis

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“…Other effects of DG are also possible; it has been shown to prevent protein glycosylation and, thereby, induce an unfolded protein response/endoplasmatic reticulum stress (9). DG has been shown to be a radiosensitizer for pancreatic cancer cells (10) and to potentiate clinical radiation effects in gliomas (11). We have previously reported that DG can potentiate the antiproliferative effects of several different classes of antineoplastic agents, thereby showing that potentiation is not necessarily linked to DNA-damaging agents (12).…”

Section: Introductionmentioning

confidence: 99%

Ovarian carcinoma cells with low levels of β-F1-ATPase are sensitive to combined platinum and 2-deoxy-d-glucose treatment

Hernlund

Hjerpe²,

Åvall‐Lundqvist³

et al. 2009

Molecular Cancer Therapeutics

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We have here examined chemopotentiating effects of glycolysis inhibitor 2-deoxy-D-glucose (DG) in two epithelial ovarian carcinoma (EOC) cell lines and 17 freshly isolated ascitic EOC cell samples, and we identify low expression of the β-F1-ATPase involved in mitochondrial ATP production as a candidate marker for sensitivity to this strategy. Although in the majority of samples, DG per se did not induce apoptosis, cotreatment with DG potentiated apoptosis and total antiproliferative effects of cisplatin and, to a lesser degree, carboplatin. In the cell lines, combination treatment with DG and cisplatin or carboplatin at noninhibitory concentrations prevented posttreatment regrowth in drug-free medium over a total of 5 days. DG per se allowed complete recuperation in drug-free medium. The more platinum-resistant a cell line was, the more sensitive it was to potentiation by DG and showed higher glucose uptake, DG-sensitive lactate production, and lower β-F1-ATPase levels. In the ascitic samples, DG reduced the median IC 50 for cisplatin by 68% and, in the most sensitive samples, up to 90%, and DG-mediated potentiation correlated with low expression of β-F1-ATPase. By contrast, cisplatin sensitivity did not correlate with β-F1-ATPase levels. The findings validate targeting cancer cell glucose metabolism for potentiating platinum chemotherapy in EOC and indicate that reduced β-F1-ATPase/oxidative phosphorylation distinguishes cells that are amenable to this strategy.

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2-Deoxy-d-glucose causes cytotoxicity, oxidative stress, and radiosensitization in pancreatic cancer

Cited by 134 publications

References 23 publications

A catabolic block does not sufficiently explain how 2-deoxy-d-glucose inhibits cell growth

A catabolic block does not sufficiently explain how 2-deoxy-d-glucose inhibits cell growth

Induction of the Warburg effect by Kaposi's sarcoma herpesvirus is required for the maintenance of latently infected endothelial cells

Ovarian carcinoma cells with low levels of β-F1-ATPase are sensitive to combined platinum and 2-deoxy-d-glucose treatment

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