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Pharmacology Research & Perspectives Feb 2024Our previous work has shown a synergistic tumoricidal efficacy of combining the hexokinase (HK) inhibitor 2-deoxyglucose (2-DG) and the autophagy inhibitor chloroquine...
Our previous work has shown a synergistic tumoricidal efficacy of combining the hexokinase (HK) inhibitor 2-deoxyglucose (2-DG) and the autophagy inhibitor chloroquine (CQ) through intraperitoneal injections on HK2-addicted prostate cancers in animal models. The pharmacokinetic (PK) behaviors of these oral drugs after simultaneous oral administration have not been reported. We developed high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) analytical methods for 2-DG and the clinically favored drug hydroxychloroquine (HCQ) for sera samples. Using a jugular vein-cannulated male rat model with serial blood collection before and after a single gavage dose of each drug alone or in combination, we examined their PK metrics for drug-drug interactions. The data demonstrated a rapid and complete separation of 2-DG from common monosaccharides by HPLC-MS-MS multi-reaction monitoring. Application of the HPLC-MS-MS 2-DG and HCQ methods to sera samples of nine rats showed a peak time (T ) for 2-DG of 0.5 h after 2-DG alone or with HCQ and identical post-peak half-life of approximately 1 h. With a seemingly bi-modal time course for HCQ, the T for HCQ alone (1.2 h) was faster than that for the combination (2 h; p = .017). After combination dosing, the peak concentration (C ) and area under the curve (AUC ) of 2-DG were decreased by 53.8% (p = .0004) and 53.7% (p = .0001), whereas AUC for HCQ was decreased by 30.8% (p = .0279) from the respective single dosing. Without changing the mean residence time (MRT ) of each drug, the combination affected the apparent volume of distribution (V ) and clearance (CL) of 2-DG, and CL for HCQ without affecting its V . We observed significant negative PK interactions, probably at the intestinal absorption level, between 2-DG and HCQ taken simultaneously by mouth. Future optimization efforts are warranted for their combination regimen for clinical translation.
Topics: Male; Rats; Animals; Hydroxychloroquine; Chromatography, High Pressure Liquid; Liquid Chromatography-Mass Spectrometry; Administration, Oral; Deoxyglucose
PubMed: 38294142
DOI: 10.1002/prp2.1173 -
American Journal of Physiology. Cell... Feb 2024Thoracic aortic aneurysm/dissection (TAAD) is a lethal vascular disease, and several pathological factors participate in aortic medial degeneration. We previously...
Thoracic aortic aneurysm/dissection (TAAD) is a lethal vascular disease, and several pathological factors participate in aortic medial degeneration. We previously discovered that the complement C3a-C3aR axis in smooth muscle cells promotes the development of thoracic aortic dissection (TAD) through regulation of matrix metalloproteinase 2. However, discerning the specific complement pathway that is activated and elucidating how inflammation of the aortic wall is initiated remain unknown. We ascertained that the plasma levels of C3a and C5a were significantly elevated in patients with TAD and that the levels of C3a, C4a, and C5a were higher in acute TAD than in chronic TAD. We also confirmed the activation of the complement in a TAD mouse model. Subsequently, knocking out Cfb (Cfb) or C4 in mice with TAD revealed that the alternative pathway and Cfb played a significant role in the TAD process. Activation of the alternative pathway led to generation of the anaphylatoxins C3a and C5a, and knocking out their receptors reduced the recruitment of inflammatory cells to the aortic wall. Moreover, we used serum from wild-type mice or recombinant mice Cfb as an exogenous source of Cfb to treat Cfb KO mice and observed that it exacerbated the onset and rupture of TAD. Finally, we knocked out Cfb in the FBN1 Marfan-syndrome mice and showed that the occurrence of TAA was reduced. In summary, the alternative complement pathway promoted the development of TAAD by recruiting infiltrating inflammatory cells. Targeting the alternative pathway may thus constitute a strategy for preventing the development of TAAD. The alternative complement pathway promoted the development of TAAD by recruiting infiltrating inflammatory cells. Targeting the alternative pathway may thus constitute a strategy for preventing the development of TAAD.
Topics: Humans; Mice; Animals; Complement Pathway, Alternative; Matrix Metalloproteinase 2; Aortic Aneurysm, Thoracic; Aortic Dissection; Inflammation; Azides; Deoxyglucose
PubMed: 38189133
DOI: 10.1152/ajpcell.00210.2023 -
Cancer Letters Dec 2014Cancer cells are characterized by altered glucose metabolism known as the Warburg effect in which aerobic glycolysis is increased. Glucose is converted to lactate even... (Review)
Review
Cancer cells are characterized by altered glucose metabolism known as the Warburg effect in which aerobic glycolysis is increased. Glucose is converted to lactate even under sufficient oxygen tension. Interfering with this process may be a potential effective strategy to cause cancer cell death because these cells rely heavily on glucose metabolism for survival and proliferation. 2-Deoxy-D-glucose (2DG), a glucose analog, targets glucose metabolism to deplete cancer cells of energy. In addition, 2DG increases oxidative stress, inhibits N-linked glycosylation, and induces autophagy. It can efficiently slow cell growth and potently facilitate apoptosis in specific cancer cells. Although 2DG itself has limited therapeutic effect in many types of cancers, it may be combined with other therapeutic agents or radiotherapy to exhibit a synergistic anticancer effect. In this review, we describe the Warburg effect and discuss 2DG and its underlying mechanisms and potential application for cancer treatment.
Topics: Autophagy; Cell Death; Cell Line, Tumor; Deoxyglucose; Glucose; Humans; Molecular Targeted Therapy; Neoplasms; Oxidative Stress
PubMed: 25218591
DOI: 10.1016/j.canlet.2014.09.003 -
Journal of Neuroendocrinology Jul 2019Information about metabolic status arrives in the brain in the form of a complex milieu of circulating signalling factors, including glucose and fatty acids, ghrelin,...
Information about metabolic status arrives in the brain in the form of a complex milieu of circulating signalling factors, including glucose and fatty acids, ghrelin, leptin and insulin. The specific interactions between humoural factors, brain sites of action and how they influence behaviour are largely unknown. We have previously observed interactions between glucose availability and the actions of ghrelin mediated via the agouti-related peptide neurones of the hypothalamus. In the present study, we examine whether these effects generalise to another ghrelin-sensitive brain nucleus, the ventral tegmental area (VTA). We altered glucose availability by injecting mice with glucose or 2-deoxyglucose i.p. to induce hyperglycaemia and glucopenia, respectively. Thirty minutes later, we injected ghrelin in the VTA. Glucose administration suppressed intra-VTA ghrelin-induced feeding. Leptin, a longer-term signal of positive energy balance, did not affect intra-VTA ghrelin-induced feeding. 2-Deoxyglucose and ghrelin both increased food intake in their own right and, together, they additively increased feeding. These results add support to the idea that calculation of metabolic need depends on multiple signals across multiple brain regions and identifies that VTA circuits are sensitive to the integration of signals reflecting internal homeostatic state and influencing food intake.
Topics: Animals; Blood Glucose; Deoxyglucose; Eating; Ghrelin; Glucose; Mice, Inbred C57BL; Ventral Tegmental Area
PubMed: 30742723
DOI: 10.1111/jne.12696 -
PLoS Genetics Jul 2020Yeast and fast-growing human tumor cells share metabolic similarities in that both cells use fermentation of glucose for energy and both are highly sensitive to the...
Yeast and fast-growing human tumor cells share metabolic similarities in that both cells use fermentation of glucose for energy and both are highly sensitive to the glucose analog 2-deoxyglucose. Spontaneous mutations in S. cerevisiae that conferred resistance to 2-deoxyglucose were identified by whole genome sequencing. Missense alleles of the HXK2, REG1, GLC7 and SNF1 genes were shown to confer significant resistance to 2-deoxyglucose and all had the potential to alter the activity and or target selection of the Snf1 kinase signaling pathway. All three missense alleles in HXK2 resulted in significantly reduced catalytic activity. Addition of 2DG promotes endocytosis of the glucose transporter Hxt3. All but one of the 2DG-resistant strains reduced the 2DG-mediated hexose transporter endocytosis by increasing plasma membrane occupancy of the Hxt3 protein. Increased expression of the DOG (deoxyglucose) phosphatases has been associated with resistance to 2-deoxyglucose. Expression of both the DOG1 and DOG2 mRNA was elevated after treatment with 2-deoxyglucose but induction of these genes is not associated with 2DG-resistance. RNAseq analysis of the transcriptional response to 2DG showed large scale, genome-wide changes in mRNA abundance that were greatly reduced in the 2DG resistant strains. These findings suggest the common adaptive response to 2DG is to limit the magnitude of the response. Genetic studies of 2DG resistance using the dominant SNF1-G53R allele in cells that are genetically compromised in both the endocytosis and DOG pathways suggest that at least one more mechanism for conferring resistance to this glucose analog remains to be discovered.
Topics: Deoxyglucose; Endocytosis; Energy Metabolism; Gene Expression Regulation, Fungal; Glucose; Glucose Transport Proteins, Facilitative; Hexokinase; Humans; Mutation; Phosphoric Monoester Hydrolases; Protein Phosphatase 1; Protein Serine-Threonine Kinases; RNA, Messenger; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Signal Transduction; Whole Genome Sequencing
PubMed: 32673313
DOI: 10.1371/journal.pgen.1008484 -
Molecular Biology of the Cell Oct 2022Endothelia determine blood-to-tissue solute delivery, yet glucose transit is poorly understood. To illuminate mechanisms, we tracked [H]-2-deoxyglucose (2-DG) in human...
Endothelia determine blood-to-tissue solute delivery, yet glucose transit is poorly understood. To illuminate mechanisms, we tracked [H]-2-deoxyglucose (2-DG) in human adipose-tissue microvascular endothelial cells. 2-DG uptake was largely facilitated by the glucose transporters GLUT1 and GLUT3. Once in the cytosol, >80% of 2-DG became phosphorylated and ∼20% incorporated into glycogen, suggesting that transported glucose is readily accessible to cytosolic enzymes. Interestingly, a fraction of intracellular 2-DG was released over time (15-20% over 30 min) with slower kinetics than for uptake, involving GLUT3. In contrast to intracellular 2-DG, the released 2-DG was largely unphosphorylated. Glucose release involved endoplasmic reticulum-resident translocases/phosphatases and was stimulated by adrenaline, consistent with participation of glycogenolysis and glucose dephosphorylation. Surprisingly, the fluorescent glucose derivative 2-NBD-glucose (2-NBDG) entered cells largely via fluid phase endocytosis and exited by recycling. 2-NBDG uptake was insensitive to GLUT1/GLUT3 inhibition, suggesting poor influx across membranes. 2-NBDG recycling, but not 2-DG efflux, was sensitive to N-ethyl maleimide. In sum, by utilizing radioactive and fluorescent glucose derivatives, we identified two parallel routes of entry: uptake into the cytosol through dedicated glucose transporters and endocytosis. This reveals the complex glucose handling by endothelial cells that may contribute to glucose delivery to tissues.
Topics: Deoxyglucose; Endothelial Cells; Epinephrine; Glucose; Glucose Transporter Type 1; Glucose Transporter Type 3; Glycogen; Humans; Maleimides; Phosphoric Monoester Hydrolases
PubMed: 35921166
DOI: 10.1091/mbc.E22-04-0146 -
Biochemical Pharmacology Nov 2014The use of energy restriction mimetic agents (ERMAs) to selectively target cancer cells addicted to glycolysis could be a promising therapeutic approach.... (Review)
Review
The use of energy restriction mimetic agents (ERMAs) to selectively target cancer cells addicted to glycolysis could be a promising therapeutic approach. Thiazolidinediones (TZDs) are synthetic agonists of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)γ that were developed to treat type II diabetes. These compounds also display anticancer effects which appear mainly to be independent of their PPARγ agonist activity but the molecular mechanisms involved in the anticancer action are not yet well understood. Results obtained on ciglitazone derivatives, mainly in prostate cancer cell models, suggest that these compounds could act as ERMAs. In the present paper, we introduce how compounds like 2-deoxyglucose target the Warburg effect and then we discuss the possibility that the PPARγ-independent effects of various TZD could result from their action as ERMAs.
Topics: Antineoplastic Agents; Apoptosis; Autophagy; Cell Line, Tumor; Deoxyglucose; Energy Metabolism; Humans; Neoplasms; Thiazolidinediones
PubMed: 25083915
DOI: 10.1016/j.bcp.2014.07.021 -
American Journal of Physiology.... Oct 2022A portion of absorbed dietary triglycerides (TG) is retained in the intestine after the postprandial period, within intracellular and extracellular compartments. This...
A portion of absorbed dietary triglycerides (TG) is retained in the intestine after the postprandial period, within intracellular and extracellular compartments. This pool of TG can be mobilized in response to several stimuli, including oral glucose. The objective of this study was to determine whether oral glucose must be absorbed and metabolized to mobilize TG in rats and whether high-fat feeding, a model of insulin resistance, alters the lipid mobilization response to glucose. Lymph flow, TG concentration, TG output, and apolipoprotein B48 (apoB48) concentration and output were assessed after an intraduodenal lipid bolus in rats exposed to the following intraduodenal administrations 5 h later: saline (placebo), glucose, 2-deoxyglucose (2-DG, absorbed but not metabolized), or glucose + phlorizin (intestinal glucose absorption inhibitor). Glucose alone, but not 2-DG or glucose + phlorizin treatments, stimulated lymph flow, TG output, and apoB48 output compared with placebo. The effects of glucose in high-fat-fed rats were similar to those in chow-fed rats. In conclusion, glucose must be both absorbed and metabolized to enhance lymph flow and intestinal lipid mobilization. This effect is qualitatively and quantitatively similar in high-fat- and chow-fed rats. The precise signaling mechanism whereby enteral glucose enhances lymph flow and mobilizes enteral lipid remains to be determined. Glucose potently enhances mesenteric lymph flow in chow- and high-fat-fed rats. The magnitude of glucose effect on lymph flow is no different in chow- and high-fat-fed rats. Glucose must be absorbed and metabolized to enhance lymph flow and mobilize intestinal lipid.
Topics: Animals; Apolipoprotein B-48; Chylomicrons; Deoxyglucose; Glucose; Lymph; Phlorhizin; Rats; Triglycerides
PubMed: 35916412
DOI: 10.1152/ajpgi.00095.2022 -
Virology Journal May 2023Increased glucose uptake and utilization via aerobic glycolysis are among the most prominent hallmarks of tumor cell metabolism. Accumulating evidence suggests that...
BACKGROUND
Increased glucose uptake and utilization via aerobic glycolysis are among the most prominent hallmarks of tumor cell metabolism. Accumulating evidence suggests that similar metabolic changes are also triggered in many virus-infected cells. Viral propagation, like highly proliferative tumor cells, increases the demand for energy and macromolecular synthesis, leading to high bioenergetic and biosynthetic requirements. Although significant progress has been made in understanding the metabolic changes induced by viruses, the interaction between host cell metabolism and arenavirus infection remains unclear. Our study sheds light on these processes during lymphocytic choriomeningitis virus (LCMV) infection, a model representative of the Arenaviridae family.
METHODS
The impact of LCMV on glucose metabolism in MRC-5 cells was studied using reverse transcription-quantitative PCR and biochemical assays. A focus-forming assay and western blot analysis were used to determine the effects of glucose deficiency and glycolysis inhibition on the production of infectious LCMV particles.
RESULTS
Despite changes in the expression of glucose transporters and glycolytic enzymes, LCMV infection did not result in increased glucose uptake or lactate excretion. Accordingly, depriving LCMV-infected cells of extracellular glucose or inhibiting lactate production had no impact on viral propagation. However, treatment with the commonly used glycolytic inhibitor 2-deoxy-D-glucose (2-DG) profoundly reduced the production of infectious LCMV particles. This effect of 2-DG was further shown to be the result of suppressed N-linked glycosylation of the viral glycoprotein.
CONCLUSIONS
Although our results showed that the LCMV life cycle is not dependent on glucose supply or utilization, they did confirm the importance of N-glycosylation of LCMV GP-C. 2-DG potently reduces LCMV propagation not by disrupting glycolytic flux but by inhibiting N-linked protein glycosylation. These findings highlight the potential for developing new, targeted antiviral therapies that could be relevant to a wider range of arenaviruses.
Topics: Humans; Lymphocytic choriomeningitis virus; Glycosylation; Glycoproteins; Lymphocytic Choriomeningitis; Deoxyglucose
PubMed: 37259080
DOI: 10.1186/s12985-023-02082-3 -
Movement Disorders : Official Journal... Oct 2022Lewy body diseases (LBDs), which are pathologically defined as the presence of intraneuronal α-synuclein (α-Syn) inclusions called Lewy bodies, encompass Parkinson's...
BACKGROUND
Lewy body diseases (LBDs), which are pathologically defined as the presence of intraneuronal α-synuclein (α-Syn) inclusions called Lewy bodies, encompass Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies. Autopsy studies have shown that the olfactory bulb (OB) is one of the regions where Lewy pathology develops and initiates its spread in the brain.
OBJECTIVE
This study aims to clarify how Lewy pathology spreads from the OB and affects brain functions using nonhuman primates.
METHODS
We inoculated α-Syn preformed fibrils into the unilateral OBs of common marmosets (Callithrix jacchus) and performed pathological analyses, manganese-enhanced magnetic resonance imaging, and F-fluoro-2-deoxy-d-glucose positron emission tomography up to 6 months postinoculation.
RESULTS
Severe α-Syn pathology was observed within the olfactory pathway and limbic system, while mild α-Syn pathology was seen in a wide range of brain regions, including the substantia nigra pars compacta, locus coeruleus, and even dorsal motor nucleus of the vagus nerve. The brain imaging analyses showed reduction in volume of the OB and progressive glucose hypometabolism in widespread brain regions, including the occipital lobe, and extended beyond the pathologically affected regions.
CONCLUSIONS
We generated a novel nonhuman primate LBD model with α-Syn propagation from the OB. This model suggests that α-Syn propagation from the OB is related to OB atrophy and cerebral glucose hypometabolism in LBDs. © 2022 International Parkinson and Movement Disorder Society.
Topics: Animals; Callithrix; Deoxyglucose; Glucose; Lewy Body Disease; Manganese; Olfactory Bulb; Parkinson Disease; alpha-Synuclein
PubMed: 35989519
DOI: 10.1002/mds.29161