Combining 2-deoxy-D-glucose with electron transport chain blockers: A double-edged sword

Boutros, Jean A.

doi:10.4161/cbt.8.13.8869

Cited by 10 publications

(8 citation statements)

References 14 publications

(14 reference statements)

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“…inhibition of recycling of NAD+ (43), inhibition of de novo pyrimidine biosynthesis (44), ROS(45) and, disruption of MMP leading to Bax/Bak oligomerisation (38). Indeed, uridine supplementation could only modestly rescue the cell death caused by rotenone and antimycin treatment in these cells (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Targeting mTORC1–Mediated Metabolic Addiction Overcomes Fludarabine Resistance in Malignant B Cells

Sharma

Janocha

Hill

et al. 2014

Molecular Cancer Research

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mTORC1 activation occurs frequently in cancers, yet clinical efficacy of rapalogs is limited due to the associated activation of upstream survival pathways. An alternative approach is to inhibit downstream of mTORC1; therefore, acquired resistance to fludarabine (Flu), a purine analog and anti-metabolite chemotherapy, active agent for chronic lymphocytic leukemia (CLL) was investigated. Elevated phospho-p70S6K (T389), an mTORC1 activation marker, predicted Flu resistance in a panel of B-cell lines, isogenic Flu-resistant (FluR) derivatives, and primary human CLL cells. Consistent with the anabolic role of mTORC1, FluR cells had higher rates of glycolysis and oxidative phosphorylation than Flu-sensitive (FluS) cells. Rapalogs (everolimus, rapamycin), induced moderate cell death in FluR and primary CLL cells, and everolimus significantly inhibited glycolysis and oxidative phosphorylation in FluR cells. Strikingly, the higher oxidative phosphorylation in FluR cells was not coupled to higher ATP synthesis. Instead it contributed primarily to an essential, dihydroorotate dehydrogenase (DHODH) catalyzed, step in de novo pyrimidine biosynthesis. mTORC1 promotes pyrimidine biosynthesis by p70S6 kinase-mediated phosphorylation of CAD (Ser1859) and favors S-phase cell cycle progression. We found increased phospho-CAD (S1859) and higher S-phase population in FluR cells. Pharmacological inhibition of de novo pyrimidine biosynthesis using N-phosphonacetyl-L-aspartate (PALA) and leflunomide, RNAi-mediated knockdown of p70S6K, and inhibition of mitochondrial respiration were selectively cytotoxic to FluR, but not FluS cells. These results reveal a novel link between mTORC1-mediated metabolic reprogramming and Flu resistance identifying mitochondrial respiration and de novo pyrimidine biosynthesis as potential therapeutic targets. Implications This study provides the first evidence for mTORC1/p70S6K-dependent regulation of pyrimidine biosynthesis in a relevant disease setting.

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Section: Discussionmentioning

confidence: 99%

Targeting mTORC1–Mediated Metabolic Addiction Overcomes Fludarabine Resistance in Malignant B Cells

Sharma

Janocha

Hill

et al. 2014

Molecular Cancer Research

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“…Other markers include glucose-regulated protein of 78 kDa, and glucose-regulated protein of 94 kDa [6,[64][65][66]. Studies indicate that 2DG induces the up-regulation of ER stress markers, implicating glycosylation as a mechanism involved in 2DG-induced toxicity [6,51,66]. Following ER stress, the mitochondrial apoptotic pathway is triggered, involving the activation of proapoptotic Bcl-2 proteins [39].…”

Section: Interference With N-linked Glycosylation Of Proteinsmentioning

confidence: 98%

“…Increased glucose metabolism attenuates oxidative stress by detoxification of ROS and maintenance of redox homeostasis via the regeneration of NADPH from PPP and the formation of pyruvate from glycolysis [49,51]. The PPP is one of the primary pathways that create molecules with reducing power [31], and in its oxidative phase, two molecules of NADPH are generated from two molecules of NADP+, whereas the nonoxidative phase generates ribose-5-phosphate for the biosynthesis of nucleotides and nucleic acids.…”

Section: Inhibition Of Antioxidationmentioning

confidence: 99%

“…The PPP is one of the primary pathways that create molecules with reducing power [31], and in its oxidative phase, two molecules of NADPH are generated from two molecules of NADP+, whereas the nonoxidative phase generates ribose-5-phosphate for the biosynthesis of nucleotides and nucleic acids. NADPH is a provider of reducing equivalents for all glutathione-and thioredoxindependent peroxidase pathways [51], both of which are major cellular thiol antioxidants responsible for the detoxification of reactive oxygen and nitrogen species (ROS and RNS), maintenance cell redox potential, and the prevention and restoration of oxidative damage [31,40]. Pyruvate is crucial for maintaining the intracellular reduced glutathione level, suppressing superoxide production and direct scavenging of hydrogen peroxide [52,53].…”

Section: Inhibition Of Antioxidationmentioning

confidence: 99%

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2-Deoxy-D-glucose targeting of glucose metabolism in cancer cells as a potential therapy

et al. 2014

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“…A natural possibility would be to concurrently inhibit the mitochondria themselves through the use of electron transport chain decouplers such as antimycin A or rotenone. It has previously been shown that the combination of 2DG and these compounds makes cells more sensitive to 2DG by increasing ROS, as glucose may act as an inhibitor of ROS production, and decreasing available NADPH in the pentose phosphate shunt [41,42]. Increased ROS may be exploited through radiation therapy in conjunction with 2DG as previously described [32].…”

Section: Discussionmentioning

confidence: 93%

Glycolysis inhibition by 2-deoxy-d-glucose reverts the metastatic phenotype in vitro and in vivo

Sottnik

Lori

Rose

et al. 2011

Clin Exp Metastasis

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Metastasis is the primary cause of death from many tumors, and novel anti-metastatic therapies are necessary. Recently, we showed that metastatic tumors down-regulate key oxidative phosphorylation (OXPHOS) genes in favor of glycolysis, a further enhancement of the Warburg effect. Therefore, we sought to determine if restriction of glycolysis using 2-deoxy-D-glucose (2DG) would lead to increased utilization of OXPHOS and inhibition of the metastatic phenotype. Noncytotoxic concentrations of 2DG dose-dependently inhibited in vitro migration and invasion in the highly metastatic DLM8-luc-M1 osteosarcoma (OS) cell line, as well as other metastatic human, canine, and murine cancer cells of different histotypes. This was associated with cytoskeletal rearrangement and inhibition of cathepsin L expression. A dose-dependent shift toward OXPHOS was confirmed by demonstrating increased oxygen utilization and decreased lactate production in 2DG treated cells. Finally, 2DG treatment significantly delayed metastasis and prolonged survival in an orthotopic postsurgical OS model. In conclusion, this work suggests that forcing cells away from glycolysis may inhibit key components of the metastatic phenotype, providing a novel avenue for metastasis prevention.

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Combining 2-deoxy-D-glucose with electron transport chain blockers: A double-edged sword

Cited by 10 publications

References 14 publications

Targeting mTORC1–Mediated Metabolic Addiction Overcomes Fludarabine Resistance in Malignant B Cells

Targeting mTORC1–Mediated Metabolic Addiction Overcomes Fludarabine Resistance in Malignant B Cells

2-Deoxy-D-glucose targeting of glucose metabolism in cancer cells as a potential therapy

Glycolysis inhibition by 2-deoxy-d-glucose reverts the metastatic phenotype in vitro and in vivo

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