2-Deoxy-D-glucose explained

2-Deoxy--glucose is a glucose molecule which has the 2-hydroxyl group replaced by hydrogen, so that it cannot undergo further glycolysis. As such; it acts to competitively inhibit the production of glucose-6-phosphate from glucose at the phosphoglucoisomerase level (step 2 of glycolysis).[1] 2-Deoxyglucose labeled with tritium or carbon-14 has been a popular ligand for laboratory research in animal models, where distribution is assessed by tissue-slicing followed by autoradiography, sometimes in tandem with either conventional or electron microscopy.

2-DG is up taken by the glucose transporters of the cell.[2] Therefore, cells with higher glucose uptake, for example tumor cells, have also a higher uptake of 2-DG. Since 2-DG hampers cell growth, its use as a tumor therapeutic has been suggested, and in fact, 2-DG is in clinical trials.[3] It is not completely clear how 2-DG inhibits cell growth. The fact that glycolysis is inhibited by 2-DG, seems not to be sufficient to explain why 2-DG treated cells stop growing.[4] A synergistic effect between 2-DG and various other agents have been reported in the pursuit of anticancer strategies.[5] [6] [7] Because of its structural similarity to mannose, 2DG has the potential to inhibit N-glycosylation in mammalian cells and other systems, and as such induces ER stress and the Unfolded Protein Response (UPR) pathway.[8] [9] [10]

Use in optical imaging

2-DG has been used as a targeted optical imaging agent for fluorescent in vivo imaging.[11] [12] In clinical medical imaging (PET scanning), fluorodeoxyglucose is used, where one of the 2-hydrogens of 2-deoxy-D-glucose is replaced with the positron-emitting isotope fluorine-18, which emits paired gamma rays, allowing distribution of the tracer to be imaged by external gamma camera(s). This is increasingly done in tandem with a CT function which is part of the same PET/CT machine, to allow better localization of small-volume tissue glucose-uptake differences.

Indian adoption for COVID-19 treatment

On May 8, 2021, the Drugs Controller General of India approved an oral formulation of 2-deoxy-D-glucose for emergency use as adjunct therapy in moderate to severe coronavirus patients.[13] [14] The drug was developed by the DRDO along with Dr. Reddy's Laboratories, who jointly claimed via a press release, that the drug "helps in faster recovery of hospitalised patients and reduces supplemental oxygen dependence".[15] [16] The Wire as well as The Hindu noted that the approval was based on poor evidence; no journal publication (or preprint) concerning efficacy and safety are yet available.

See also

References

  1. Wick . AN . Drury . DR . Nakada . HI . Wolfe . JB . 1957 . Localization of the primary metabolic block produced by 2-deoxyglucose . J Biol Chem. 224 . 2. 963–969 . 10.1016/S0021-9258(18)64988-9 . 13405925. free .
  2. Laussel. Clotilde. Léon. Sébastien. December 2020. Cellular toxicity of the metabolic inhibitor 2-deoxyglucose and associated resistance mechanisms. Biochemical Pharmacology. en. 182. 114213. 10.1016/j.bcp.2020.114213. 32890467 . free.
  3. Pelicano . H . Martin . DS . Xu . RH . Huang . P . 2006 . Glycolysis inhibition for anticancer treatment . Oncogene . 25 . 34. 4633–4646 . 10.1038/sj.onc.1209597 . 16892078. Glycolysis . 22155169 .
  4. 10.1073/pnas.0803090105. 19004802. 2584745. A catabolic block does not sufficiently explain how 2-deoxy-D-glucose inhibits cell growth. Proceedings of the National Academy of Sciences. 105. 46. 17807–17811. 2008. Ralser. M.. Wamelink. M. M.. Struys. E. A.. Joppich. C.. Krobitsch. S.. Jakobs. C.. Lehrach. H.. 2008PNAS..10517807R. free.
  5. Cheng . Gang . Zielonka . Jacek . Dranka . Brian P. . McAllister . Donna . Mackinnon . A. Craig . Joseph . Joy . Kalyanaraman . Balaraman . 2012-05-15 . Mitochondria-Targeted Drugs Synergize with 2-Deoxyglucose to Trigger Breast Cancer Cell Death . Cancer Research . en . 72 . 10 . 2634–2644 . 10.1158/0008-5472.CAN-11-3928 . 0008-5472 . 3700358 . 22431711.
  6. Luo . Zhangyi . Xu . Jieni . Sun . Jingjing . Huang . Haozhe . Zhang . Ziqian . Ma . Weina . Wan . Zhuoya . Liu . Yangwuyue . Pardeshi . Apurva . Li . Song . March 2020 . Co-delivery of 2-Deoxyglucose and a glutamine metabolism inhibitor V9302 via a prodrug micellar formulation for synergistic targeting of metabolism in cancer . Acta Biomaterialia . en . 105 . 239–252 . 10.1016/j.actbio.2020.01.019 . 7105957 . 31958597.
  7. Abebe . Felagot A. . Hopkins . Megan D. . Vodnala . Suraj N. . Sheaff . Robert J. . Lamar . Angus A. . 2021-07-20 . Development of a Rapid In Vitro Screening Assay Using Metabolic Inhibitors to Detect Highly Selective Anticancer Agents . ACS Omega . en . 6 . 28 . 18333–18343 . 10.1021/acsomega.1c02203 . 2470-1343 . 8296616 . 34308064.
  8. Kurtoglu. M.. Gao. N.. Shang. J.. Maher. J. C.. Lehrman. M. A.. Wangpaichitr. M.. Savaraj. N.. Lane. A. N.. Lampidis. T. J.. 2007-11-07. 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. Molecular Cancer Therapeutics. 6. 11. 3049–3058. 10.1158/1535-7163.mct-07-0310. 18025288. 1535-7163. 6315384 .
  9. Xi. Haibin. Kurtoglu. Metin. Liu. Huaping. Wangpaichitr. Medhi. You. Min. Liu. Xiongfei. Savaraj. Niramol. Lampidis. Theodore J.. 2010-07-01. 2-Deoxy-d-glucose activates autophagy via endoplasmic reticulum stress rather than ATP depletion. Cancer Chemotherapy and Pharmacology. 67. 4. 899–910. 10.1007/s00280-010-1391-0. 20593179. 0344-5704. 3093301.
  10. Defenouillère. Quentin. Verraes. Agathe. Laussel. Clotilde. Friedrich. Anne. Schacherer. Joseph. Léon. Sébastien. 2019-09-03. The induction of HAD-like phosphatases by multiple signaling pathways confers resistance to the metabolic inhibitor 2-deoxyglucose. Science Signaling. 12. 597. eaaw8000. 10.1126/scisignal.aaw8000. 31481524. 201829818. 1945-0877.
  11. 10.1016/j.ab.2008.09.050 . 18938129 . Characterization and performance of a near-infrared 2-deoxyglucose optical imaging agent for mouse cancer models . Analytical Biochemistry . 384 . 2 . 254–262 . 2009 . Kovar . Joy L. . Volcheck . William . Sevick-Muraca . Eva . Simpson . Melanie A. . Olive . D. Michael . 2720560 .
  12. Cheng, Z., Levi, J., Xiong, Z., Gheysens, O., Keren, S., Chen, X., and Gambhir, S., Bioconjugate Chemistry, 17(3), (2006), 662-669
  13. https://economictimes.indiatimes.com/industry/healthcare/biotech/pharmaceuticals/what-is-2-deoxy-d-glucose-2-dg-and-is-it-effective-against-covid/articleshow/82567938.cms?from=mdr What is 2-deoxy-D-glucose (2-DG) and is it effective against Covid?
  14. Web site: 2021-05-08. DCGI approves anti-COVID drug developed by DRDO for emergency use. 2021-05-09. Press Information Bureau, Government of India. en-IN.
  15. Web site: Borana. Ronak. 2021-05-12. India's Drug Regulator Has Approved DRDO's New COVID Drug on Missing Evidence. 2021-05-18. The Wire Science. en-GB.
  16. News: Koshy. Jacob. 2021-05-11. Questions remain on DRDO's COVID drug. en-IN. The Hindu. 2021-05-18. 0971-751X.

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