2DG Through the Years

Decoding The Warburg Effect: Understanding Cancer’s Energy Needs

In the early 1920s, Otto Warburg (Nobel laureate) made an important observation, a fundamental difference between normal cells and cancer cells in how they make energy. All cells, particularly tumor cells, need enormous amounts of energy to survive and grow.

The reason? The Warburg Effect tells us that cancer cells rely on a process called glycolysis (the breakdown of the sugar glucose for energy) even when oxygen is available.

Cancer cells consume sugar at rates hundreds of times higher than normal. Tumors require more energy than normal tissue due to adaptive alterations in metabolism, which leads to their uncontrolled growth. This observation led to the Warburg Effect, which explains that cancer cells primarily rely on glycolysis — a process that breaks down sugar for energy — even when oxygen is available. This dependence on glucose makes glycolysis a key target in this case making 2-Deoxy-D-glucose (2DG) for cancer an attractive option.

Normal cells can burn fats and proteins for energy, using oxygen as a catalyst; but in conditions of low-oxygen, cancer cells prefer to metabolize sugars. When 2DG enters the scene – fooling them into grabbing it instead of glucose – they can’t make use of oxygen to turn sugar into energy, as they would in the normal pathway of glycolysis.

What happens is that 2DG tricks cancer cells into using it as if it were just ‘normal’ glucose. This tricks the cancer cells into using the glucose because it stalls their ability to metabolize sugar normally. This process deprives the cancer cells of their energy source, resulting in a marked increase in the tumor\’s natural cell death (apoptosis).

Personification of Warburg researching cancer metabolism. Origins of 2DG 2-deoxy-D-glucose research.

2DG: A Hidden Gem in Cancer Treatment

2DG is a relatively inexpensive, safe compound whose potential has been known for decades. It has a long track record of safety, and a long history of research and use. Sadly, this compound has been largely underused, simply because it is non‑patentable, which has dissuaded pharma from investing in its development.

The journey of 2DG began over 60 years ago, with its application in PET-CT scans demonstrating its selective absorption by tumors. In these scans, 2DG is tagged with a radioactive tracer, highlighting its uptake in cancer cells.

It acts as a sugar analogue and marks glucose uptake areas in tumors by coloring cancer cells with a radioactive tracer dye. 2DG uptake and anti-cancer selectivity highlights its potential as a cancer treatment.

2DG in clinical studies shows its potential to target tumors precisely makes it a promising candidate therapy. However, without the financial backing from major pharmaceutical companies, 2DG has struggled to reach broader clinical use despite its efficacy and safety.

2DG in Modern Medicine: Beyond Cancer

In 2021, 2DG has found applications beyond cancer treatment. During the COVID-19 pandemic, India approved 2DG for emergency use to treat moderate to severe cases of the COVID-19 virus. This decision was based on its ability to inhibit the replication of virus-infected cells that have extremely high rates of sugar metabolism, showcasing its versatility.

Thousands of patients have used 2DG safely, reinforcing its potential as a multi-faceted therapeutic agent. Despite its proven efficacy and safety, the lack of patentability and financial incentives has kept 2DG in the shadows of more profitable treatments. It is a natural therapeutic for both cancer and viral infections.

The Promise of 2DG in Cancer Research

For over three decades, 2DG has been the focus of significant cancer research, particularly through the work of Dr. Theodore Lampidis at the University of Miami Miller School of Medicine. Dr. Lampidis has dedicated his career to understanding the metabolic processes of cancer cells and exploiting their glucose dependency.

His pioneering studies demonstrate that 2DG can starve cancer cells and shut down their growth – and that some of the cells will die from apoptosis, leaving no trace of the tumor. With National Cancer Institute funding, Lampidis has shown that 2DG doesn’t just work as an anti-cancer agent in and of itself but can augment other therapies as well.

By exploiting the metabolic weakness of cancer cells, potentially as a powerful stand-alone treatment or through synergistic combinations with existing therapies, 2DG could prove to be nothing less than an extraordinary new type of deadly cancer medicine. And then maybe, one day, it will become a standard of care. 2DG still has a long way to go, but this could be the story of a drug that was there, on the brink of being the real deal, and that never went to the starting block.

So, if we continue to be guided by these insights, and to explore the enormous potential for smart use of 2DG, it will lead to an adjustment in treatment strategies that will give thousands of patients a chance for survival.

References

The Warburg Effect and its Importance for Cancer:

  • Warburg, O. (1956). On the origin of cancer cells. Science, 123(3191), 309-314. Available at: NCBI
  • Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646-674. Available at: NCBI

Overview of 2DG as a Potential Anti-Cancer Treatment:

  • Zhang, D., et al. (2014). 2-Deoxy-D-glucose targeting of glucose metabolism in cancer cells as a potential therapy. Cancer Letters, 355(2), 176-183. Available at: NCBI
  • Raez, L. E., et al. (2013). A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors. Cancer Chemotherapy and Pharmacology, 71(2), 523-530. Available at: NCBI
  • Stein, M., et al. (2010). Targeting tumor metabolism with 2-deoxyglucose in patients with advanced cancer. Cancer Biology & Therapy, 9(11), 903-910. Available at: NCBI

2DG as an Anti-COVID Drug:

  • Dwarakanath, B. S., et al. (2021). 2-Deoxy-D-glucose (2-DG): From cancer to COVID-19 therapy. Journal of Cancer Research and Therapeutics, 17(3), 2-10. Available at: NCBI
  • BBC (2021). India approves 2-DG drug for emergency use in COVID-19 treatment. Available at: BBC

Dr. Theodore Lampidis\’ Work on 2DG for Cancer:

  • Lampidis, T. J., et al. (2006). The anticancer agent 2-deoxyglucose downregulates multiple cell-cycle regulatory proteins by inhibiting N-linked glycosylation in the NCI/ADR-RES cancer cell line. Molecular Cancer Therapeutics, 5(3), 728-734. Available at: NCBI
  • Aft, R. L., et al. (2002). Evaluation of 2-deoxy-D-glucose as a chemotherapeutic agent: mechanism of cell death. British Journal of Cancer, 87(7), 805-812. Available at: NCBI
  • Singh, D., et al. (2015). The metabolic targeting of cancer cells by 2-deoxyglucose combined with inhibition of autophagy: Enhanced efficacy in glucose-addicted cells. Cancer Research, 75(18 Supplement), 1047-1047. Available at: NCBI

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