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International Journal of Molecular... Dec 2019The ability of 2-deoxy-d-glucose (2-DG) to interfere with d-glucose metabolism demonstrates that nutrient and energy deprivation is an efficient tool to suppress cancer... (Review)
Review
The ability of 2-deoxy-d-glucose (2-DG) to interfere with d-glucose metabolism demonstrates that nutrient and energy deprivation is an efficient tool to suppress cancer cell growth and survival. Acting as a d-glucose mimic, 2-DG inhibits glycolysis due to formation and intracellular accumulation of 2-deoxy-d-glucose-6-phosphate (2-DG6P), inhibiting the function of hexokinase and glucose-6-phosphate isomerase, and inducing cell death. In addition to glycolysis inhibition, other molecular processes are also affected by 2-DG. Attempts to improve 2-DG's drug-like properties, its role as a potential adjuvant for other chemotherapeutics, and novel 2-DG analogs as promising new anticancer agents are discussed in this review.
Topics: Cell Death; Combined Modality Therapy; Deoxyglucose; Glioblastoma; Glucose; Glucose-6-Phosphate; Glucose-6-Phosphate Isomerase; Glycolysis; Hexokinase; Humans
PubMed: 31905745
DOI: 10.3390/ijms21010234 -
Neuron Sep 2023Intermittent fasting (IF) is a diet with salutary effects on cognitive aging, Alzheimer's disease (AD), and stroke. IF restricts a number of nutrient components,...
Intermittent fasting (IF) is a diet with salutary effects on cognitive aging, Alzheimer's disease (AD), and stroke. IF restricts a number of nutrient components, including glucose. 2-deoxyglucose (2-DG), a glucose analog, can be used to mimic glucose restriction. 2-DG induced transcription of the pro-plasticity factor, Bdnf, in the brain without ketosis. Accordingly, 2-DG enhanced memory in an AD model (5xFAD) and functional recovery in an ischemic stroke model. 2-DG increased Bdnf transcription via reduced N-linked glycosylation, consequent ER stress, and activity of ATF4 at an enhancer of the Bdnf gene, as well as other regulatory regions of plasticity/regeneration (e.g., Creb5, Cdc42bpa, Ppp3cc, and Atf3) genes. These findings demonstrate an unrecognized role for N-linked glycosylation as an adaptive sensor to reduced glucose availability. They further demonstrate that ER stress induced by 2-DG can, in the absence of ketosis, lead to the transcription of genes involved in plasticity and cognitive resilience as well as proteostasis.
Topics: Humans; Deoxyglucose; Alzheimer Disease; Brain-Derived Neurotrophic Factor; Glucose; Stroke; Ketosis; Activating Transcription Factor 4
PubMed: 37453419
DOI: 10.1016/j.neuron.2023.06.013 -
Journal of Cellular and Molecular... May 2019It is well established that cancer cells depend upon aerobic glycolysis to provide the energy they need to survive and proliferate. However, anti-glycolytic agents have...
It is well established that cancer cells depend upon aerobic glycolysis to provide the energy they need to survive and proliferate. However, anti-glycolytic agents have yielded few positive results in human patients, in part due to dose-limiting side effects. Here, we discovered the unexpected anti-cancer efficacy of Polydatin (PD) combined with 2-deoxy-D-glucose (2-DG), which is a compound that inhibits glycolysis. We demonstrated in two breast cell lines (MCF-7 and 4T1) that combination treatment with PD and 2-DG induced cell apoptosis and inhibited cell proliferation, migration and invasion. Furthermore, we determined the mechanism of PD in synergy with 2-DG, which decreased the intracellular reactive oxygen (ROS) levels and suppressed the PI3K/AKT pathway. In addition, the combined treatment inhibited the glycolytic phenotype through reducing the expression of HK2. HK2 deletion in breast cancer cells thus improved the anti-cancer activity of 2-DG. The combination treatment also resulted in significant tumour regression in the absence of significant morphologic changes in the heart, liver or kidney in vivo. In summary, our study demonstrates that PD synergised with 2-DG to enhance its anti-cancer efficacy by inhibiting the ROS/PI3K/AKT/HIF-1α/HK2 signalling axis, providing a potential anti-cancer strategy.
Topics: Animals; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Deoxyglucose; Enzymes; Female; Glucosides; Glycolysis; Hexokinase; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; MCF-7 Cells; Mice, Inbred BALB C; Molecular Structure; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction; Stilbenes; Xenograft Model Antitumor Assays
PubMed: 30920152
DOI: 10.1111/jcmm.14276 -
Molecules (Basel, Switzerland) Apr 2021Theranostics is a precision medicine which integrates diagnostic nuclear medicine and radionuclide therapy for various cancers throughout body using suitable tracers and... (Review)
Review
Theranostics is a precision medicine which integrates diagnostic nuclear medicine and radionuclide therapy for various cancers throughout body using suitable tracers and treatment that target specific biological pathways or receptors. This review covers traditional theranostics for thyroid cancer and pheochromocytoma with radioiodine compounds. In addition, recent theranostics of radioimmunotherapy for non-Hodgkin lymphoma, and treatment of bone metastasis using bone seeking radiopharmaceuticals are described. Furthermore, new radiopharmaceuticals for prostatic cancer and pancreatic cancer have been added. Of particular, F-18 Fluoro-2-Deoxyglucose (FDG) Positron Emission Tomography (PET) is often used for treatment monitoring and estimating patient outcome. A recent clinical study highlighted the ability of alpha-radiotherapy with high linear energy transfer (LET) to overcome treatment resistance to beta--particle therapy. Theranostics will become an ever-increasing part of clinical nuclear medicine.
Topics: Animals; Fluorodeoxyglucose F18; Humans; Neoplasms; Positron Emission Tomography Computed Tomography; Radioisotopes; Therapeutics
PubMed: 33924345
DOI: 10.3390/molecules26082232 -
Current Genetics Feb 2021Yeast and cancer cells are metabolically similar as they use fermentation of glucose as a primary means of generating energy. Reliance on glucose fermentation makes both... (Review)
Review
Yeast and cancer cells are metabolically similar as they use fermentation of glucose as a primary means of generating energy. Reliance on glucose fermentation makes both of these cell types highly sensitive to the toxic glucose analog, 2-deoxyglucose. Here we review the cellular and metabolic pathways that play a role in 2-deoxyglucose sensitivity and discuss how the modifications to these pathways result in acquisition of 2-deoxyglucose resistance. Insights gained from genetic and proteomic studies in yeast provide new ideas for the design of combinatorial therapies for cancer treatment.
Topics: DNA Damage; Deoxyglucose; Endocytosis; Glucose; Metabolic Networks and Pathways; Proteomics; Saccharomyces cerevisiae
PubMed: 33136227
DOI: 10.1007/s00294-020-01122-7 -
Annales de Biologie Clinique Jul 2022The thoracic aortic aneurysm corresponds to the dilation of the ascending part of the aorta, which can lead to a dissection (TAAD for Thoracic Aortic Aneurysm and... (Review)
Review
The thoracic aortic aneurysm corresponds to the dilation of the ascending part of the aorta, which can lead to a dissection (TAAD for Thoracic Aortic Aneurysm and Dissection) or aortic rupture. The etiologies are diverse, but in approximately 20% of cases a genetic origin is found. About thirty genes are reported to be responsible for the development of TAAD. The majority of these genes encode for proteins involved in the extracellular matrix, the contraction of smooth muscle cells or the growth factor TGF-β signaling pathway. Identifying the pathogenic variant responsible for the aortic disease becomes essential to make a definitive diagnosis, to guide and to personalize the treatment of the patients but also to screen relatives at risk. The availability and access to genetic testing have improved considerably with the development of new sequencing techniques (NGS for Next Generation Sequencing) and the use of gene panels. This review summarizes the main genes associated with TAAD as well as the current diagnostic strategy.
Topics: Aortic Dissection; Aortic Aneurysm, Thoracic; Azides; Deoxyglucose; Genetic Testing; Humans
PubMed: 36099351
DOI: 10.1684/abc.2022.1742 -
Seminars in Nuclear Medicine Nov 202118F-Fluoro-deoxyglucose positron emission computed tomography (18F-FDG PET CT) is an established modality used mainly in oncology. Though it has widespread oncologic... (Review)
Review
18F-Fluoro-deoxyglucose positron emission computed tomography (18F-FDG PET CT) is an established modality used mainly in oncology. Though it has widespread oncologic indications, it is not tumor specific. Apart from the physiological distribution, uptake of FDG may be seen in many benign conditions, including infection and inflammation in children and adults. Performing and acquiring a technically adequate PET CT study may be more challenging in children. Proper preparation and an acceptable imaging protocol will help to avoid re-acquisition and in minimizing the radiation exposure. Sound knowledge of the physiological variants and benign conditions that are specific to the pediatric population will aid in correct interpretation of the PET CT study. It is important that radiologists and Nuclear Medicine physicians who report these studies are well-acquainted with these pitfalls to avoid false positive studies.
Topics: Adult; Child; Fluorodeoxyglucose F18; Humans; Neoplasms; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Radiopharmaceuticals
PubMed: 34243902
DOI: 10.1053/j.semnuclmed.2021.06.007 -
Anesthesia and Analgesia Apr 2016
Topics: Anesthetics, Inhalation; Animals; Antimetabolites; Deoxyglucose; Humans
PubMed: 26991630
DOI: 10.1213/ANE.0000000000001177 -
Seminars in Radiation Oncology Jan 2019Dysregulated glucose and redox metabolism are near universal features of cancers. They therefore represent potential selectively toxic metabolic targets. This review... (Review)
Review
Dysregulated glucose and redox metabolism are near universal features of cancers. They therefore represent potential selectively toxic metabolic targets. This review outlines the preclinical and clinical data for targeting glucose and hydroperoxide metabolism in cancer, with a focus on drug strategies that have the most available evidence. In particular, inhibition of glycolysis using 2-deoxyglucose, and inhibition of redox metabolism using the glutathione pathway inhibitor buthionine sulfoximine and the thioredoxin pathway inhibitor auranofin, have shown promise in preclinical studies to increase sensitivity to chemotherapy and radiation by increasing intracellular oxidative stress. Combined inhibition of glycolysis, glutathione, and thioredoxin pathways sensitizes highly glycolytic, radioresistant cancer models in vitro and in vivo. Although the preclinical data support this approach, clinical data are limited to exploratory trials using a single drug in combination with either chemotherapy or radiation. Open research questions include optimizing drug strategies for targeting glycolysis and redox metabolism, determining the appropriate timing for administering this therapy with concurrent chemotherapy and radiation, and identifying biomarkers to determine the cancers that would benefit most from this approach. Given the quality of preclinical evidence, dual targeting of glycolysis and redox metabolism in combination with chemotherapy and radiation should be further evaluated in clinical trials.
Topics: Animals; Auranofin; Buthionine Sulfoximine; Deoxyglucose; Glucose; Glycolysis; Humans; Hydrogen Peroxide; Neoplasms; Oxidation-Reduction; Oxidative Stress; Radiation-Sensitizing Agents
PubMed: 30573182
DOI: 10.1016/j.semradonc.2018.10.007 -
Seminars in Cancer Biology Apr 2018Reactive 1,2-dicarbonyl compounds (DCs) are generated from carbohydrates during food processing and storage and under physiological conditions. In the recent decades,... (Review)
Review
Reactive 1,2-dicarbonyl compounds (DCs) are generated from carbohydrates during food processing and storage and under physiological conditions. In the recent decades, much knowledge has been gained concerning the chemical formation pathways and the role of DCs in food and physiological systems. DCs are formed mainly by dehydration and redox reactions and have a strong impact on the palatability of food, because they participate in aroma and color formation. However, they are precursors of advanced glycation end products (AGEs), and cytotoxic effects of several DCs have been reported. The most abundant DCs in food are 3-deoxyglucosone, 3-deoxygalactosone, and glucosone, predominating over methylglyoxal, glyoxal, and 3,4-dideoxyglucosone-3-ene. The availability for absorption of individual DCs is influenced by the release from the food matrix during digestion and by their reactivity towards constituents of intestinal fluids. Some recent works suggest formation of DCs from dietary sugars after their absorption, and others indicate that certain food constituents may scavenge endogenously formed DCs. First works on the interplay between dietary DCs and diseases reveal an ambiguous role of the compounds. Cancer-promoting but also anticancer effects were ascribed to methylglyoxal. Further work is still needed to elucidate the reactions of DCs during intestinal digestion and pathophysiological effects of dietary DCs at doses taken up with food and in "real" food matrices in disease states such as diabetes, uremia, and cancer.
Topics: Carbohydrates; Deoxyglucose; Dietary Exposure; Food; Galactose; Glyoxal; Humans; Ketoses; Oxidation-Reduction; Oxidative Stress
PubMed: 29174601
DOI: 10.1016/j.semcancer.2017.11.014