Can We Control Sugar Metabolism in Cancer Cells?

Can We Control Sugar (Glucose) Metabolism In Cancer Cells: Basics Of 2DG And Mechanism Of Action

Cancer cells have some important hallmarks, one being aerobic glycolysis or increased glucose metabolism compared to normal cells. It is essential to control the glucose metabolism in these cells to prevent the metastasis of cancer cells around the neighboring tissues. Because glucose is an integral component for cell proliferation, cancer cells cannot proliferate and hence cannot invade other tissues when there is a depletion of glucose. For this purpose, we have discussed a vital glucose analog, 2-deoxy-D-Glucose (2-DG), that can be used for cancerous cells to control sugar metabolism. This 2-DG binds with the glucose transporters at the place of glucose because of structural similarity. It moves into the cancer cells, which cannot be metabolized like glucose. This glucose analog can be used separately and is also being used in combination with different therapies, as discussed in detail later in this article. 2-DG binds with the glucose transporters at the place of average glucose, thus inhibiting the binding and transport of glucose in the cell. 2-DG cannot be metabolized to produce ATP or Pyruvate. It deprives the cancer cells of nutrients and glucose, increasing the activity of Caspase 3 and PARP, the main components to induce apoptosis in the cell. 


Cancer cells need more energy to produce ATP than normal cells because they have a high proliferation rate. For this purpose, cancer cells go through glycolysis even in the presence of oxygen by a phenomenon termed the Warburg effect or aerobic glycolysis. They have an increased number of Glucose transporters like GluT1 and uptake more glucose, as is required for their maintenance and growth. This will suppress the mechanism of apoptosis or cell death in the malignant cells that occur in normal cells.


This increased glucose concentration by tumor cells may lead to metastasis, disruption of mitochondria because of increased oxidative stress, and hypoxia. It has been found that if the nutrient concentration in the cancer cells gets depleted by any process, this will cause cell death. It is impossible to finish cancer cells with oxygen and nutrients, but it is possible to treat organisms using glucose analogs like 2-DG that will inhibit glucose metabolism in cancer cells, reducing cell proliferation and growth. That is a comparatively non-toxic and effective therapy leading to apoptosis of selective cells. 


To target glucose metabolism in the tumor cells, a glucose analog, 2-deoxy-D-glucose (2DG), is being used widely for experimental purposes and at the clinical level. This glucose analog binds the glucose transporter and inhibits the transport of glucose. It is then converted to 2-DG-6-phosphate by Hexokinase enzyme. This 2-DG-6-phosphate cannot be metabolized any further; hence, the production of ATP and NADH in cancer cells will decrease.



2-DG can also cause oxidative stress in the cell by disrupting the glycosylation process, resulting in the misfolding of proteins. This also induces alterations in the expression of genes, inactivation of different proteins involved in cell signaling pathways, and causes movement of Calcium into the cell that will induce tumor cell death by apoptosis. This 2-DG may also lead to the reduction of cell proliferation in tumors. 


2-DG is also combined with different anticancer agents in cancer therapeutics like radiotherapy. It increases the apoptosis of cancerous cells selectively when used with radiotherapy. In this regard, many experiments have been performed on different tumor cell lines and animal models. Human cervical cancer cell lines (HeLa) were used to check the effect of 2-DG in combination with radiation therapy. It was found that the cancer cells were deprived of glucose 8 hours after the treatment of radiation and 2-DG. This led to the death of metastatic cells due to glucose and nutrient deprivation. It was also found that any disruption in thiol metabolism can lead to cell toxicity using thiol antioxidants like NAC. Experiments showed that the effects of 2-DG were more severe for the transformed or cancerous cells than those of normal cells.


2-DG can be used in combination with L-buthionine- [S, R]-sulfoximine (BSO) drug that is given to cancer patients as a therapy because it targets the Glutamate Cysteine Ligase (GCL) enzyme, which is a rate-limiting enzyme involved in the synthesis of Glutathione. Glutathione is an important enzyme protecting cells from damage caused by reactive oxygen species. When tumor cells are treated with 2-DG in addition to this drug, this downregulates the level of GCL enzyme in tumor cells, causing oxidative stress in the cancer cells and malignant cell death by apoptosis.


Cisplatin can also be used in combination with glucose analog 2-DG; it is an anti-cancerous agent being used as a drug to treat different types of cancers, especially head and neck cancer. It is used either alone or in combination with other therapies, such as anti-tumor drugs or radiotherapies. Cisplatin has different side effects, so it is not being used for clinical trials yet. Cisplatin inhibits the replication of DNA as well as the transcription of various genes involved in cell proliferation and survival, thus leading to cell death. If cisplatin is used in combination with 2-DG, it will not only increase the oxidative stress in cancer cells but also lead to cancer cell death. Different experiments have been performed to prove this hypothesis. 


2-DG is also being used in combination with different chemotherapeutic agents, these free radicals increase the production of reactive oxygen species within the cancerous cells. In breast cancer cells, it has been found that ROS causes Taxol toxicity. Taxols are used as a chemotherapeutic agent in breast cancer patients. This could be overcome when chemotherapeutic drugs are combined with 2-DG, a promising therapy for breast and lung cancer patients.


Different assays are used to measure the viability of cells. Experiments have shown that the cancer cells, when treated with 2-DG, show a greater concentration of glucose transporters at the start, increasing the uptake of 2-DG binding glucose transporters. This 2-DG targets Caspase-3 and Poly A Polymerase (PARP) enzyme, involved in inducing cell death by cleaving DNA, thus depriving cancer cells of nutrients and inducing the process of apoptosis.

The effect of 2-DG on cancer cells can be checked using the MTT assay, which determines the type of dead cells undergoing apoptosis. 2-DG mainly targets the caspases that are active enzymes playing a role in apoptosis. Usually, caspase three and PARP enzyme activity is measured to check if cells have undergone apoptosis. PARP enzyme is involved in the cleavage of DNA during the process of apoptosis. It was found through experiments that when cancer cells are treated with 2-DG, both the Caspase 3 and the PARP activity is increased, thus increasing the process of apoptosis in these cells. 


The levels of GluT-1 transporter protein can also be checked in cancer cells after treatment with 2-DG to study the effects of glucose analog. Experiments have shown that the transformed cells have increased levels of glucose transporter proteins as compared to the untransformed cells. Because more significant the number of glucose transporters in a cell, the more the number of 2-DG will bind to them, being the glucose analog. This will inhibit the binding of glucose molecules, thus depriving the cells of glucose and nutrients. When cancer cells do not have enough glucose and nutrients, they cannot proliferate rapidly, an essential hallmark of cancer cells, and hence cannot grow properly. Thus, moving toward cell death.


2-DG has become an essential aspect of cancer therapeutics study because of its two critical properties, the inhibition of glycolysis by 2-DG and its accumulation in the cancer cells. Because of these properties, it is used as an anticancer therapeutic agent in cancer patients. When cancer cells are treated with 2-DG, they undergo a stress response at the start, which causes an increase in the number of glucose transporter proteins like GluT1, causing increased movement of 2-DG into the cells decreased intake of normal glucose molecules. Thus, diminishing the glucose and nutrient concentration in these cells and inducing apoptosis. 

Further, 2-DG can also be used with other anticancer therapies like radiotherapy and chemotherapy to exhibit a synergistic anticancer effect. Different assays are being used to check the results of 2-DG on cancer cells.



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