Chemotherapy is an essential therapeutic strategy used for many years to treat cancer patients. But the chemotherapeutic drugs used have many side effects on the patient body. The tumor size may get reduced after the treatment. But it reoccurs in the patient after some time. To overcome these limitations of Chemotherapy. We have discussed combining therapy, glucose antimetabolite called 2-deoxy-D-glucose, and Chemotherapy. This shows more effective results.
We have discussed many in vitro, in vivo, clinical trials, and human experiments to prove that 2DG can make Chemotherapy more effective because of its inhibitory nature.
Glucose is an essential ingredient in the cell that provides energy for organisms’ survival and helps cells grow and proliferate. Normal cells require a smaller amount of glucose than malignant cells, which need a more significant amount of glucose to meet their needs. They have higher glucose metabolism than normal cells because they have more substantial proliferation and metastasis abilities. Aerobic respiration converts this glucose to pyruvate and, ultimately, ATP (Xi et al., 2014).
To overcome metastasis and reduce the proliferation capacity of cancer cells, it has been found that we should control the sugar metabolism in these cells. For this purpose, some glucose antimetabolite should be used that helps control or inhibit the glycolytic pathway in malignant cells. 2-deoxy-D-glucose (2DG) is a very effective antimetabolite for glucose in this regard. 2-deoxy-D-glucose or 2DG binds the glucose transporter proteins like GluT1 in the cell because of its structural similarity with glucose. When it binds to the transporter proteins, it does not allow normal glucose molecules to bind and enter the cell. This results in cells that are deprived of glucose and ultimately deprived of energy.
As the cells cannot produce ATP, they will not grow and proliferate properly. Further, 2DG activates the apoptotic pathway in these cells by activating Caspase 3 and the PARP enzymes. That result in the killing of tumor cells. Moreover, cells cannot undergo any event without glucose, which converts normal cells into malignant cells (Xi et al., 2014).
Therapeutic Modalities for Cancer
Many therapeutic modalities are being used to help cancer patients recover from the disease. Like Chemotherapy, radiotherapy, etc., in addition to these, 2DG is also used either alone, given to the patient orally or intravenously, or used in combination with other therapeutic strategies like radiation therapy and Chemotherapy.
Chemotherapy is a standard therapy used to treat all types of cancer, particularly breast cancer in women. It results in a reduction in the size of the tumor before the patient undergoes surgery to delete it. It is commonly called preoperative Chemotherapy or PCT. However, it does not result in a complete pathologic response, and the tumor may reoccur in the patient after some time (Martoni et al., 2010).
2DG as an adjuvant to Chemotherapy
It is found in different experiments that 2-deoxy-D-glucose (2DG) can be used in combination with Chemotherapy to make it more effective. This combinational therapy will result in a complete pathologic response in cancer patients. For this purpose, many in vitro and in vivo experiments have been performed. So 2DG can be used as an adjuvant in Chemotherapy to increase the effectiveness of the therapeutic modality (Martoni et al., 2010).
In vitro Experiments
In vitro studies on cancer cell lines were performed to check the safety and efficacy of the combination therapy. Cell lines were grown in the laboratory. And then, some cell lines were treated with some chemotherapeutic agents alone, while the others were given chemotherapeutic drugs and 2-deoxy-D-glucose.
Results of In Vitro Experiments
The cell lines treated with the chemotherapeutic drugs only show a reduction in tumor size but not all the cancer cells were damaged by this treatment. However, the cell lines injected with 2DG and the chemotherapeutic drugs show more effective results. In this case, all the malignant cells were destroyed after therapy.
As the cells respond to damage caused to them by using any radiation or chemical treatment. For this purpose, they need energy in the form of ATP. When 2DG is injected into the cancer cells, they cannot produce enough energy. 2DG binds the glucose transporters in the cell. Glucose cannot enter the cell, and the glycolytic pathway is inhibited, so there is no pyruvate or ATP production. When a cell is deprived of nutrients and energy, it cannot respond to the damage caused by any treatment. Hence 2DG increases the effectiveness of Chemotherapy when given as a chemotherapy adjuvant to patients (Dwarakanath, 2009).
In Vivo Experiments
Similar experiments were performed in vivo on animal models to check the effectiveness of Chemotherapy and compare it with combinational therapy.
The effects of the chemotherapeutic drug Adriamycin (ADR) effects were studied using mice models of human carcinomas. In the experiment, three mice groups were studied. One group was used as a control; the second group was given Adriamycin drug alone, while the third animal group was given the drug along with 2DG (Maher et al., 2004).
Results of In Vivo Experiments
It was observed that the second group, that was given the drug alone, showed lower efficacy as compared to the third group which was also injected with 2DG. The second group showed recurrence of the tumor after some time because of the presence of the large amount of glucose in the cells that helped them recover the damage caused by the drug. However, in the third group that was given the drug as well as 2DG, the effects or damages caused to the cells by the drug could not be overcome by cells because of energy deprivation. 2DG doesn’t allow the cells to take up glucose, hence there is no production of energy in these cells that will not allow cells to undergo repair biochemical processes within them to recover from the damage (Maschek et al., 2004).
Clinical Trials to Check Safety and Efficacy of Treatment
Clinical trials on humans were performed to check the safety and efficacy of this combinational therapy i.e.: chemotherapeutic drugs and 2-deoxy-D-glucose. Many volunteers participated in the trials. The volunteers were given docetaxel drug and 2DG based on their body weight. The results were observed after some time. It was seen that the patients have increased blood glucose levels at the start when 2DG was given orally along with the drug. They also suffered from nausea and dizziness. But this side effect disappeared after a few hours. So, the side effects of this glucose antimetabolite are tolerable by the patients (Raez et al., 2013).
Moreover, patients that were given chemotherapeutic drugs and the glycolytic pathway inhibitor 2DG showed more effective results. As the cancer cells cannot recover from damage caused by the drug when they are injected with 2DG because of glucose deprivation in them. Moreover, it was found through experiments that 2DG only affects the malignant cells without any harm to the normal body cells of the patient. So, this combinational therapy is safer and more effective as compared to previously available therapeutic modalities (Raez et al., 2013).
Cancer cells require a greater amount of glucose and energy because of their higher proliferation rate. The metastasis and proliferation of cancer cells can be controlled by controlling the sugar metabolism in these cells. And to control the glucose metabolism in a cell, we need to inhibit the glycolytic pathway so that there is no production of pyruvate and ATP in the cell. Glucose antimetabolites are inhibitors of the glycolytic pathway, and these can be used as they have structural similarities with the glucose molecule. 2-deoxy-D-glucose is one of the most important glucose antimetabolites that binds the GluT1 glucose transporter. However, it cannot be metabolized in the cell, hence no energy production. Cells become deprived of energy leading to no proliferation and metastasis.
Chemotherapy has been a therapeutic modality for years to treat cancer patients, and the drugs used may have many side effects. Moreover, they do not show a complete pathogenic response in the patient. Moreover, the tumor may reoccur in person after some time.
To overcome these limitations of Chemotherapy, we have discussed many experiments that show that combining Chemotherapy and 2DG is a more effective and safer therapeutic strategy than chemotherapeutic drugs alone. The use of this combinational therapy will completely kill tumor cells.
“Dwarakanath, B. S. (2009). Cytotoxicity, radiosensitization, and chemosensitization of tumor cells by 2-deoxy-D-glucose in vitro. Journal of Cancer Research and Therapeutics, 5 Suppl 1, 27–31. https://doi.org/10.4103/0973-1482.55137
Maher, J. C., Krishan, A., & Lampidis, T. J. (2004). Greater cell cycle inhibition and cytotoxicity induced by 2-deoxy-D-glucose in tumor cells treated under hypoxic vs aerobic conditions. Cancer Chemotherapy and Pharmacology, 53(2), 116–122. https://doi.org/10.1007/s00280-003-0724-7
Martoni, A. A., Zamagni, C., Quercia, S., Rosati, M., Cacciari, N., Bernardi, A., Musto, A., Fanti, S., Santini, D., & Taffurelli, M. (2010). Early 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography may identify a subset of patients with estrogen receptor-positive breast cancer who will not respond optimally to preoperative Chemotherapy. Cancer, 116(4), 805–813. https://doi.org/10.1002/cncr.24820
Maschek, G., Savaraj, N., Priebe, W., Braunschweiger, P., Hamilton, K., Tidmarsh, G. F., De Young, L. R., & Lampidis, T. J. (2004). 2-Deoxy-D-glucose Increases the Efficacy of Adriamycin and Paclitaxel in Human Osteosarcoma and Non-Small Cell Lung Cancers in Vivo. Cancer Research, 64(1), 31–34. https://doi.org/10.1158/0008-5472.CAN-03-3294
Raez, L. E., Papadopoulos, K., Ricart, A. D., Chiorean, E. G., Dipaola, R. S., Stein, M. N., Rocha Lima, C. M., Schlesselman, J. J., Tolba, K., Langmuir, V. K., Kroll, S., Jung, D. T., Kurtoglu, M., Rosenblatt, J., & Lampidis, T. J. (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. https://doi.org/10.1007/s00280-012-2045-1
Xi, H., Kurtoglu, M., & Lampidis, T. J. (2014). The wonders of 2-deoxy-d-glucose. IUBMB Life, 66(2), 110–121. https://doi.org/10.1002/iub.1251″
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