Effects of 2-deoxy-D-glucose on glycolysis, proliferation kinetics and radiation response of human cancer cells

Jain, Varsha; Kalia, V.K.; Sharma, Ruchi; Maharajan, Veeramani; Menon, Malini

doi:10.1016/0360-3016(85)90117-8

Cited by 99 publications

(61 citation statements)

References 24 publications

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“…44 Thus, available evidences support the hypothesis that the effects of 2-DG could be mediated through the reduction in drug efflux process leading to higher drug retention and energy linked modification of the repair and fixation of etoposideinduced lesions by altering the supply of metabolic energy required for these processes. 25,26,[45][46][47][48] Since, 2-DG reduces the flow of metabolic energy more drastically in tumor cells, 2-DG can significantly enhance the cytotoxicity of etoposide in tumor cells by inhibiting the repair and recovery processes. Indeed, 2-DG induced inhibition of DNA repair following irradiation has been reported in several human and murine tumor cells.…”

Section: Discussionmentioning

confidence: 99%

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

Gupta

Mathur

Dwarakanath

2005

Cancer Biology & Therapy

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Section: Discussionmentioning

confidence: 99%

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

Gupta

Mathur

Dwarakanath

2005

Cancer Biology & Therapy

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“…For example, high concentrations of 2-DG sensitize malignant glioma cells or HeLa to radiation. Interestingly, the use of 2-DG did not promote radiotoxicity of normal peripheral blood leukocytes, splenocytes or thymocytes (Kalia et al, 1982;Jain et al, 1985;Dwarkanath et al, 2001;Swamy et al, 2005). Moreover, the same results were obtained in animal experiments.…”

Section: -Dg Sensitizes To Radio-and Chemotherapymentioning

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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“…Although these EGFR-TKIs were shown to be effective in patients with advanced non-small cell lung cancer (NSCLC) harboring EGFRactivating mutations such as small in-frame deletions in exon 19 or the L858R missense mutation in exon 21, patients almost always develop resistance to these agents, most commonly through the acquisition of a secondary T790M mutation in EGFR exon 20 (6). To date, there is no standard therapeutic option for patients with acquired resistance to reversible EGFR TKIs due to acquisition of EGFR T790M (7).…”

Section: Introductionmentioning

confidence: 99%

Glycolysis Inhibition Sensitizes Non–Small Cell Lung Cancer with T790M Mutation to Irreversible EGFR Inhibitors via Translational Suppression of Mcl-1 by AMPK Activation

Kim

Yun

Hong

et al. 2013

Molecular Cancer Therapeutics

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The secondary EGF receptor (EGFR) T790M is the most common mechanism of resistance to reversible EGFR-tyrosine kinase inhibitors (TKI) in patients with non-small cell lung cancer (NSCLC) with activating EGFR mutations. Although afatinib (BIBW2992), a second-generation irreversible EGFR-TKI, was expected to overcome the acquired resistance, it showed limited efficacy in a recent phase III clinical study. In this study, we found that the inhibition of glycolysis using 2-deoxy-D-glucose (2DG) improves the efficacy of afatinib in H1975 and PC9-GR NSCLC cells with EGFR T790M. Treatment with the combination of 2DG and afatinib induced intracellular ATP depletion in both H1975 and PC9-GR cells, resulting in activation of AMP-activated protein kinase (AMPK). AMPK activation played a central role in the cytotoxicity of the combined treatment with 2DG and afatinib through the inhibition of mTOR. The alteration of the AMPK/mTOR signaling pathway by the inhibition of glucose metabolism induced specific downregulation of Mcl-1, a member of the antiapoptotic Bcl-2 family, through translational control. The enhancement of afatinib sensitivity by 2DG was confirmed in the in vivo PC9-GR xenograft model. In conclusion, this study examined whether the inhibition of glucose metabolism using 2DG enhances sensitivity to afatinib in NSCLC cells with EGFR T790M through the regulation of the AMPK/mTOR/Mcl-1 signaling pathway. These data suggest that the combined use of an inhibitor of glucose metabolism and afatinib is a potential therapeutic strategy for the treatment of patients with acquired resistance to reversible EGFR-TKIs due to secondary EGFR T790M.

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Effects of 2-deoxy-D-glucose on glycolysis, proliferation kinetics and radiation response of human cancer cells

Cited by 99 publications

References 24 publications

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

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

Sugar-free approaches to cancer cell killing

Glycolysis Inhibition Sensitizes Non–Small Cell Lung Cancer with T790M Mutation to Irreversible EGFR Inhibitors via Translational Suppression of Mcl-1 by AMPK Activation

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