2-Deoxy-D-Glucose can Improve Radiotherapy, Study Shows

Can 2-deoxy-D-glucose (2DG) Make Radiation Therapy More Effective

Introduction 

Cancer cells have many hallmarks that differentiate them from normal cells. One of them is that the malignant cells have a high glucose metabolism rate as compared to those of normal cells. Because tumor cells have increased proliferation ability and growth rate, they need more energy in the form of ATP. Hence, they use more glucose to produce ATP and pyruvate. To control the proliferation and metastasis of malignant cells, we need to control the sugar metabolism in these cells (Singh et al., 2005). 

Many therapeutic modalities like radiotherapy and chemotherapy have been used for years to control the metastasis of cancer cells in neighboring tissues. But these strategies should be modified from time to time to make them even more effective. As the cancer cells become resistant to current therapies, so there is a need to use some combinational therapies to overcome this resistance. A glucose analog called 2-deoxy-D-glucose (2DG) has been found to be very effective when used in combination with previously known therapeutic strategies. 2DG has structural similarity with the normal glucose molecule, so it can bind to the glucose transporters within the cell at the place of normal glucose. But it is not metabolized by enzymes like normal glucose and acts as a competitive inhibitor. Thus, ATP and pyruvate will not be produced by the process of glycolysis. When cancer cells become deprived of nutrients or glucose, they cannot proliferate and grow anymore. So, their metastasis can be controlled in this way. 2DG only affects the malignant cells without any harm to normal cells, which increases its safety and efficacy (Aiestaran-Zelaia et al., 2022). 

Radiation Therapy as a Therapeutic Modality

2DG is being used alone to control the sugar metabolism in malignant cells, and it is also used in combination with Radiotherapy and Chemotherapy. Radiotherapy is an important therapeutic modality to cure cancer patients, as almost 60% of cancer patients receive this therapy either alone or in combination with chemotherapy. But it has many side effects on the patient body, either the malignant cells become resistant to radiation after some time, or the patient’s normal cells are also affected causing severe damage leading to the paralysis of brain cells. Behavioral changes have also been observed in those patients who have undergone radiotherapy. So, to overcome this resistance in cancer cells for radiation therapy and to keep the normal body cells safe from the damaging effects of radiation, we need to use some glycolytic inhibitors so that malignant cells cannot repair the damage that is caused by radiation due to lack of energy and nutrients and become dead. 

2-deoxy-D-glucose in combination with Radiotherapy

2DG is an important glycolytic inhibitor that binds the GluT1 glucose transporter protein and is phosphorylated by the Hexokinase enzyme, but it is not metabolized any further, inhibiting the glycolytic pathway, so there is no ATP or pyruvate production in the cancer cells which are given this competitive inhibitor of normal glucose and the glycolytic pathway. Moreover, 2DG activates caspase 3 and PARP enzymes, inducing apoptosis in the malignant cells without any harm to the normal cells. 

So, when 2-deoxy-D-glucose (2DG) is used in combination with radiotherapy in malignant cells, radiation therapy becomes more effective than when it is used alone. Because cells cannot resist the damage caused by radiation in the presence of a competitive inhibitor of glucose, 2DG, or in the absence of glucose and nutrients.

2-DG is a cytotoxic, as well as a radiosensitizing agent via a mechanism involving changes in intracellular oxidation/reduction status since oxidative stress is one possible mechanism for ionizing radiation-induced cell death.

Source ImageTargeting Glioblastoma Stem Cells with 2-Deoxy-D-Glucose (2-DG) Potentiates Radiation-Induced Unfolded Protein Response (UPR)

Experiments to check the safety and efficacy of combination therapy

Many experiments have been performed in vitro in laboratories as well as in vivo on animal models to check the effectiveness of 2DG in combination with radiotherapy which will be discussed later. Clinical trials have also been performed on humans and this combinational therapy is always found effective and safer for all cancer patients.

In vitro Experiments 

For in vitro studies, cancer cell lines were used in the laboratory to check the effect of 2DG and radiation therapy on the malignant cells. The therapeutic strategies were used alone on some cell lines while on the other cell lines, both modalities were applied at the same time. When radiation therapy was used alone on the malignant cells cultured in a laboratory, these cells reverse the effects of radiation within 48 hours after the treatment. This occurred because they have increased glucose metabolism producing a large amount of ATP and glucose, which helped the cells repair the damage caused by radiation. And the cells started proliferating and metastasizing again at the same pace. 

When the similar cell lines grown in the laboratory were treated with radiation therapy in combination with a glucose analog 2-deoxy-D-glucose (2DG), which has structural similarity with the normal glucose molecule, it was observed that the malignant cells cannot reverse the effects of radiation therapy. and the transformed cells did not proliferate anymore showing that the results of this therapy were more successful as compared to the one when radiotherapy was given alone. This occurred because the glucose analog 2DG binds the glucose transporter proteins, but cannot metabolize itself in the malignant cells, as a result, cells cannot produce enough energy to overcome the damage caused by radiation. Hence, they do not become resistant to radiation therapy and are damaged by the effects of therapy (Tower, 1958). 

In vivo Experiments and Clinical Trials

To check the efficacy of 2DG in humans, clinical trials were performed after in vitro studies. Many volunteers, either normal or cancer patients participated in the trials and were given 2DG either orally or intravenously. Some clinical side effects like hypoglycemia in tissues were observed after treating a person with 2DG, although blood glucose levels increased. As the glucose was released from the glycogen stores into the blood when its level decreased in the cells or tissues. Most of the side effects remained for 60 minutes after administration of 2DG and then disappeared. Showing no severe effects of 2DG use on the human body. These trials confirmed the safety and efficacy of 2DG so that it can be used along with other therapeutic modalities in cancer patients in the future to improve therapeutic strategies (Kurtoglu et al., 2007).

 

2DG as an adjunct to Radiation Therapy

After passing the in vitro studies results and clinical trials, 2DG is being used as an adjunct to radiation therapy in cancer patients nowadays because of its efficacy and safety. When cancer patients are given 2DG with radiotherapy either simultaneously or right after the radiation treatment, an increase in blood glucose level is observed in patients for some time. 2DG is given intravenously or orally to patients during a 25 to 60 minutes period after radiation therapy. It is given in small doses based on the body weight of the patient. Usually, the range varies from 50 to 200mg/Kg of body weight of the patient. It is observed that when 2DG is given orally to a patient, it shows fewer side effects than when it is injected intravenously into the same patient (Aghaee et al., 2012). 

More effective therapeutic strategy

Radiation therapy is more effective in patients when given in combination with 2DG because 2DG is a glycolytic inhibitor. It doesn’t allow cancer cells to reverse the damaging effects caused by radiation. 2-deoxy-D-glucose, being a glucose analog binds the GluT1 protein competitively which is a glucose transporter, and does not allow the normal glucose molecule to bind it. Normally, cancer cells use a larger amount of glucose as compared to normal cells to meet their energy needs and for metastasis and proliferation. This 2DG therapy results in low or controlled glucose metabolism in malignant cells. When cells cannot produce enough energy, they cannot overcome the damaging effects of radiation. As a result, cells will die. Moreover, 2DG only affects the transformed or malignant cells. It does not harm the normal cells of the patient. This characteristic also makes 2DG an important therapeutic modality that can be used as an adjunct to radiation therapy in cancer patients (Shah et al., 2019). 

Conclusion 

To conclude the article, many therapeutic modalities are in use for the treatment of different types of cancer. Radiotherapy is one of the effective strategies in this regard. But radiation not only damages the malignant cells but also harms the normal cells. Moreover, cancer cells may develop resistance to this therapy after some time. To overcome these complications of radiotherapy, researchers have been focusing on developing combinational therapies that will help patients overcome their side effects and make the treatment more effective. A glucose analog 2-deoxy-D-glucose (2DG) was found to be an adjunct to radiotherapy through many in vitro and in vivo experiments that makes the therapy more effective and safer when used in combination. 

When 2DG is used with radiotherapy, malignant cells cannot overcome the damage caused by radiation because of a lack of ATP. 2DG being, a glycolytic inhibitor, does not allow the cells to produce ATP as it cannot be metabolized itself. And cells cannot take up glucose because the glucose transporters are competitively bound by the structurally similar compound 2DG. When there is a lack of energy and nutrients, malignant cells cannot repair the damage caused by radiation therapy. that makes the therapy more effective. The use of 2DG along with radiation therapy is also safer because it does not harm the normal cells of the patient’s body but only the malignant or transformed cells. 

This makes 2DG a very safe and effective treatment against cancer. And the use of 2DG in combination with radiotherapy makes later a more effective therapeutic modality. 

References 

Aghaee, F., Islamian, J. P., & Baradaran, B. (2012). The combination of 2-deoxy-D-glucose and doxorubicin enhanced radiosensitivity and chemosensitivity in breast cancer cells. Journal of Breast Cancer15(2), 141–147. https://doi.org/10.4048/jbc.2012.15.2.141

Aiestaran-Zelaia, I., Sánchez-Guisado, M. J., Villar-Fernandez, M., Azkargorta, M., Fadon-Padilla, L., Fernandez-Pelayo, U., Perez-Rodriguez, D., Ramos-Cabrer, P., Spinazzola, A., Elortza, F., Ruíz-Cabello, J., & Holt, I. J. (2022). 2 deoxy-D-glucose augments the mitochondrial respiratory chain in heart. Scientific Reports12(1), 1–9. https://doi.org/10.1038/s41598-022-10168-1

Kurtoglu, M., Gao, N., Shang, J., Maher, J. C., Lehrman, M. A., Wangpaichitr, M., Savaraj, N., Lane, A. N., & Lampidis, T. J. (2007). Under normoxia, 2-deoxy-D-glucose causes cell death in select tumor types by interfering with N-linked glycosylation.

Molecular Cancer Therapeutics6(11), 3049–3058. https://doi.org/10.1158/1535-7163.MCT-07-0310

Shah, S. S., Rodriguez, G. A., Musick, A., Walters, W. M., de Cordoba, N., Barbarite, E., Marlow, M. M., Marples, B., Prince, J. S., Komotar, R. J., Vanni, S., & Graham, R. M. (2019). Targeting glioblastoma stem cells with 2-deoxy-d-glucose (2-DG) potentiates radiation-induced unfolded protein response (UPR). Cancers11(2), 1–17. https://doi.org/10.3390/cancers11020159

Singh, D., Banerji, A. K., Dwarakanath, B. S., Tripathi, R. P., Gupta, J. P., Mathew, T. L., Ravindranath, T., & Jain, V. (2005). 2-deoxy-D-glucose: Dose escalation studies in glioblastoma multiforme patients. Strahlentherapie Und Onkologie181(8), 507–514. https://doi.org/10.1007/s00066-005-1320-z

Tower, D. B. (1958). THE EFFECTS OF 2‐DEOXY‐d‐GLUCOSE ON METABOLISM OF SLICES OF CEREBRAL CORTEX INCUBATED IN VITRO. Journal of Neurochemistry3(2), 185–205. https://doi.org/10.1111/j.1471-4159.1958.tb12625.x

 

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