2-Deoxy-d-glucose: from diagnostics to therapeutics
Keywords:Glycolysis, 2-deoxy-D-glucose, SARS-CoV-2, Anticancer and antiviral therapy
Glucose is the most common source of cellular energy and a substrate for many biochemical processes. Abnormal glucose signalling has been found in many diseases including cancers and inflammatory diseases. A glucose analog, 2-deoxy-D-glucose (2DG) which interferes with the cellular glucose metabolism has shown promising results both as a diagnostic and therapeutic agent in certain diseased conditions such as cancer, cardiovascular diseases, Alzheimer disease, etc. Viral-infected cells have also been found to increase their glucose uptake and recently Drug Controller General of India (DCGI) has given approval for the therapeutic use of 2DG in managing severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection which has received worldwide attention and has been declared a public health emergency of global concern. An attempt has accordingly been made in this article to review the diagnostic and therapeutic potentials of 2-deoxy-glucose with special emphasis on to its implications in SARS-CoV-2.
DCGI approves anti-COVID drug developed by DRDO for emergency use. Available at https://pib.gov.in/PressReleasePage.aspx?PRID=1717007. Accessed on 08 May 2021.
Wick AN, Drury DR, Nakada HI, Wolfe JB. Localization of the primary metabolic block produced by 2-deoxyglucose. J Biol Chem. 1957;224(2):963-9.
Chen W, Guéron M The inhibition of bovine heart hexokinase by 2-deoxy-D-glucose-6-phosphate: characterization by 31P NMR and metabolic implications. Biochimie. 1992;74:867-73.
Demetrakopoulos GE, Linn B, Amos H. Starvation , deoxy sugars, ouabin and ATP metabolism in normal and malignant cells. Cancer Biochem Biophys. 1982;6:65-74.
Gareth SH, Brown GJ, K rauseU, Patel JV, Vertommen D, Bertrand L, et al. Activation of AMP-Activated Protein Kinase Leads to the Phosphorylation of Elongation Factor 2 and an Inhibition of Protein Synthesis. Curr Biol. 2002;12(16):1419-23.
Hardie D, Lin SC. AMP-activated protein kinase—Not just an energy sensor. F1000 Res. 2017;6:1724.
Jung CH, Ro SH, Cao J, Otto NM, Kim DH. mTOR regulation of autophagy. FEBS Lett. 2010;584:1287-95.
Shutt DC, O’Dorisio MS, Aykin-Burns N, Spitz DR. 2-deoxy-D-glucose induces oxidative stress and cell killing in human neuroblastoma cells. Cancer Biol Ther. 2010;9:853-61.
Kurtoglu M, Gao N, Shang J, Maher J.C, Lehrman M.A, Wangpaichitr M, et al. Under normoxia, 2-deoxy-D-glucose elicits cell death in select tumor types not by inhibition of glycolysis but by interfering with N-linked glycosylation. Mol Cancer Ther. 2007;6:3049-58.
Xi H, Kurtoglu M, Liu H, Wangpaichitr M, You M, Liu X, Savaraj N, Lampidis, T J. 2-Deoxy-d-glucose activates autophagy via endoplasmic reticulum stress rather than ATP depletion". Canc Chemother Pharmacol. 2010;67(4):899-910.
Xi H, Kurtoglu M, Lamipidis T.J. The wonders of 2-deoxy-D-glucose. IUBMB J. 2014;66:110-21.
Navale AM, Paranjape AN. Glucose transporters: physiological and pathological roles. Biophys Rev. 2016;8(1):5-9.
Mees G, Dierckx R, Vangestel C, Laukens D, Damme NV, De Wiele CV. Pharmacologic Activation of Tumor Hypoxia: A Means to Increase Tumor 2-Deoxy-2-[F-18] Fluoro-D-Glucose Uptake? Mol Imaging. 2013;12:49-58.
Viswanathan C, Faria S, Devine C, Patnana M, Sagebiel T, Iyer RB, Bhosale PR. [F]-2-Fluoro-2-Deoxy-D-glucose-PET Assessment of Cervical Cancer. PET Clin. 2018;13:165-77.
Kang HT, Hwang ES. 2-Deoxyglucose: An anticancer and antiviral therapeutic, but not any more a low glucose mimetic. Life Sci. 2006;78(12):1392-9.
Gupta S, Farooque A, Adhikari JS, Singh S, Dwarakanath BS. Enhancement of radiation and chemotherapeutic drug responses by 2-deoxy-D-glucose in animal tumors J Can Res Ther. 2009;5:16-20.
Aft RL, Zhang FW, Gius D. Evaluation of 2-deoxy-D-glucose as a chemotherapeutic agent: Mechanism of cell death. Br J Cancer. 2002;87:805-12.
Cao X, Fang L, Gibbs S, Huang Y, Dai Z, Wen P, Zheng X, et al. Glucose uptake inhibitor sensitizes cancer cells to daunorubicin and overcomes drug resistance in hypoxia. Cancer Chemother Pharmacol. 2007;59:495-505.
Catanzaro D, Gaude E, Orso G, Giordano C, Guzzo G, Rasola A, Ragazzi E, et al. Inhibition of glucose-6-phosphate dehydrogenase sensitizes cisplatin-resistant cells to death. Oncotarget. 2015;6(30): 30102-14.
Liberti MV, Locasale JW. The Warburg Effect: How Does it Benefit Cancer Cells? Trends in Biochemical Sciences. 2016; 41(3):211-8.
Batra S, Adekola KUA, Rosen ST, Shanmugam M. Cancer metabolism as a therapeutic target. Oncology. 2013;27:460-7.
Magier Z, Jarzyna R. The role of glucose transporters in human metabolic regulation. Postepy Biochem. 2013;59:70-82.
Defenouillère Q, Verraes A, Laussel C, Friedrich A, Schacherer J, Léon S. The induction of HAD-like phosphatases by multiple signaling pathways confers resistance to the metabolic inhibitor2-deoxyglucose.Sci Signal. 2019;12:597.
Raez LE, Papadopoulos K, Ricart AD, Chiorean EG, DiPaola RS, Stein MN. A phase I dose-escalation trial of 2-deoxy-d-glucose alone or combined with docetaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2013;71:523-30.
Singh, D, Banerji AK, Dwarakanath B S, Tripathi RP, Gupta JP, Mathew TL, et al. . Optimizing cancer radiotherapy with 2-deoxy-D-glucose. Strahlentherapie und Onkologie. 2005;181(8):507-14.
Garriga-Canut M, Schoenike B, Qazi R, Bergendahl K, Daley TJ, Pfender R M, et al. 2-Deoxy-D-glucose reduces epilepsy progression by NRSF-CtBP–dependent metabolic regulation of chromatin structure". Nat Neurosci. 2006;9(11):1382-7.
Spivack JG, Prusoff WH, Tritton TR. A study of the antiviral mechanism of action of 2-Deoxy-D-glucose: normally glycosylated proteins are not strictly required for herpes simplex virus attachment but increase viral penetration and infectivity. Virology. 1982;123:123-38 .
Passalacqua KD, Lu J, Goodfellow I, Kolawole AO, Arche JR, Maddox RJ, et al. Glycolysis is an intrinsic factor for optimal replication of a norovirus. Host Microbe Biology. 2019;10:e02175-18.
Choi SY ,Heo MJ, Lee C, Choi YM , An I, Bae S, et al. 2-deoxy-d-glucose Ameliorates Animal Models of Dermatitis. Biomedicines. 2020;8(20)1-11.
Abbound G, Choi SC, Kanda N, Spatraro LZ, Roopenian DC, Morel L. Inhibition of glycolysis reduces disease severity in an autoimmune model of rheumatoid arthritis. Front Immunol. 2018;9:1973.
Zang F, Aft RL, Chemo sensitizing and cytotoxic effects of 2-deoxy-D-glucose on breast cancer cells. J Cancer Res Ther. 2009;1:41-3.
Pajak B, Siwiak E, Sołtyka M, Priebe A, Zieliński R, Fokt I, Ziemniak M, et al. 2-Deoxy-D-Glucose and Its Analogs: From Diagnostic to Therapeutic Agents. Int J Mol Sci. 2020;21(1):234.
Sanchez EL, Lagunoff M. Viral activation of cellular metabolism. Virology. 2015;479-80.
Kilbourne EB. Inhibition of influenza virus multiplication with a glucose antimetabolite (2-deoxy-D-Glucose). Nature. 1959;183:271-2.
Codo AC, Davanzo GG , Monteiro LDB, Gabriela Souza GFD, Muraro SP, Virgilio-da-Silva JV , et al. Elevated glucose levels favor SARS-CoV-2 infection and monocyte response through a HIF-1alpha/glycolysis-dependent axis. Cell Metab. 2020;32:437-46.
Bojkova D, Klann K, Koch B, Widera M, Krause D, Ciesek S, et al. Proteomics of SARS-CoV-2-infected host cells reveals therapy targets. Nature. 2020;583:469-72.
Ardestani A, Azizi Z. Targeting glucose metabolism for treatment of COVID-19. Signal Transduction and Targeted Therapy. 2021;6:112.
Rodriguez AE, Ducker GS, Billingham LK, Weinberg SE, Rabinowiitz JD, C Chandel NS.Serine metabolism support macrophage il-1B production. Cell Metab. 2019;29(4):1003-11.
Balkrishna A, Singh S, DevS, Jain V, Varshney A. Glucose anti metabolite 2-Deoxy-D-Glucose and its derivative aspromising candidates for tackling COVID-19: Insights derived from in silico docking and molecular simulations. 2020.
Data Supporting 2DG as a possible treatment for Covid 19.Lampidis News. Lampidis Cancer Foundation, U.S.A. Available at: www.lampidisfoundation.org. Accessed on 26 March 2020.
Farooque A, Afrin F, Adhikari JS, Dwarakanath BS. Polarization of macrophages towards M1 phenotype by a combination of 2-deoxy-d-glucose and radiation: implications for tumor therapy. Immunobiology. 2016;221(2):269-81.
Farooque A, Singh N, Adhikari JS, Afrin F, Dwarakanath BS. Enhanced antitumor immunity contributes to the radio-sensitization of ehrlich ascites tumor by the glycolytic inhibitor 2-deoxy-D-glucose in mice. PLoS One. 2014;9(9):e108131.
Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130(5):2620-9.
Landau BR, Lubs HA. Animal responses to 2-deoxy-D-glucose administration. Proc Soc Exp Biol Med. 1958;99(1):124-7.
Vijayaraghavan R, Kumar D, Dube SN, Singh R, Pandey KS, Bag BC, et al. Acute toxicity and cardio-respiratory effects of 2-deoxy-D-glucose: a promising radio sensitiser. Biomed Environ Sci. 2006;19:96-103.
Verma A, Adhikary A, Woloschak G, Dwarakanath BS, Papineni RVL. A combinatorial approach of a poly pharmacological adjuvant 2-deoxy-D-glucose with low dose radiation therapy to quell the cytokine storm in COVID-19management. Int J Rad Biol. 2020;96:11.