2-DG is a glucose analogue being explored as a potential anti-cancer agent. Its mechanism of action revolves around its structural similarity to glucose, allowing it to interfere with glucose metabolism within cells. It works by inhibiting glycolysis, the primary energy pathway used by many cancer cells, thus starving them of energy and leading to cell death. Additionally, 2-DG can induce other effects like apoptosis, autophagy and increased oxidative stress, further contributing to its anti-cancer properties.
It is well documented that cancer cells utilise more energy than normal cells, and they favour glycolysis for ATP production (primary energy currency of cells) and cell metabolism. Utilisation of glycolytic energy by tumour cells even in the presence of oxygen is called aerobic glycolysis or the Warburg effect. This glucose metabolism in tumour cells shows a promising target for the regulation of the growth of cancerous cells.
Several applications of 2-DG are known for the efficient elimination of cancer cells, and the synergetic effect of 2-DG has been reported in the literature. The limited therapeutic effect of 2-DG in cancer treatment is overcome by its beneficial synergistic anti-cancer effect with other therapeutic agents or radiotherapy by blocking glycolysis in hypoxic tumour cells and subsequent cell death. 2-DG capitalises on its similarity to glucose and the tendency of cancer cells to utilise glycolysis even in the presence of oxygen, a process known as aerobic glycolysis or the Warburg effect.
Inhibiting Glycolysis: Cancer cells often exhibit a metabolic shift called the Warburg effect, relying heavily on glycolysis even in the presence of oxygen. 2-DG acts as an inhibitor of glycolysis by mimicking glucose and being taken up by cells, but then, unlike glucose, it interferes with the metabolic process, preventing the generation of energy.
Inducing Cell Death: By disrupting glycolysis, 2-DG can lead to apoptosis (programmed cell death) and autophagy (a cellular cleanup process) in cancer cells, effectively killing them.
Chemosensitisation: 2-DG can also act as a chemosensitizer, meaning it can make cancer cells more sensitive to other chemotherapeutic drugs, improving the effectiveness of traditional cancer treatments.
Other Potential Mechanisms: 2-DG may also have other mechanisms of action, such as inhibiting N-linked glycosylation (a process involved in protein modification), which can lead to endoplasmic reticulum stress and further contribute to cancer cell death.
Safety and Toxicity: 2-DG is generally considered to be a relatively safe agent for clinical use, with studies indicating it is well-tolerated and has a low level of systemic toxicity.
Clinical Trials and Future Directions: 2-DG is being evaluated in clinical trials, and research is ongoing to explore its potential in various cancer types and to develop strategies for improving its efficacy and reducing potential side effects.
2-DG was first synthesised in the 1950s. In 1978, a radioactive form, 2-deoxy-2-(fluoro-18F)-D-glucose, was created for medical imaging and became useful in medical imaging via positron emission tomography (PET) as a marker for glucose in the body. While early reports were mixed, 2-DG’s potential as a radiosensitiser and chemotherapeutic agent has gained renewed interest, particularly due to its ability to target specific metabolic pathways in cancer cells.
Glycolysis has survived a billion years of evolution dating back to a time when there was no oxygen in the atmosphere and the only means by which microbial life could sustain itself was through the breakdown of sugar (glycolysis). Applying this fundamental tenet to cancer, investigating the use of the glycolytic inhibitor 2-DG as a potential clinical agent to target chemo-resistant hypoxic cancer cells began in the late 1990s. There have been reports focused on administering 2-DG as a single high dose prior to radiation to increase the efficacy in the treatment of patients with brain cancer and it was clearly demonstrated in vitro that blocking glycolysis with 2-DG led to tumour cell death.
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