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Epigenetic and Metabolic Alterations in Cancer Cells: Mechanisms and Therapeutic Approaches
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Glycolysis is the major contributor to acetyl-CoA production in cancer cells, and glucose flux is correlated with elevated histone acetylation (Cluntun et al., 2015; Liu et al., 2015). Glycolysis blockade could therefore reverse aberrant histone acetylation. Indeed, treatment with glycolysis inhibitor 2-deoxyglucose significantly reduced intracellular acetyl CoA levels and broadly reduced histone H3, H4, H2A and H2B acetylation in multiple cancer cell lines (Liu et al., 2015). Glycolysis inhibition using, 3-bromopyruvate (GAPDH inhibitor), achieved a similar suppression of histone acetylation in embryonic stem cells, leading to cellular differentiation (Moussaieff et al., 2015). Thus, glycolysis inhibition has the potential to modulate aberrant histone acetylation.
Evaluations of cardiovascular diseases with hybrid PET-CT imaging
Published in Yi-Hwa Liu, Albert J. Sinusas, Hybrid Imaging in Cardiovascular Medicine, 2017
Antti Saraste, Sami Kajander, Juhani Knuuti
Besides combination of CTA and perfusion imaging in the detection of CAD, there are other potential approaches where hybrid PET-CT imaging could be applied. Noninvasive assessment of the presence of extensive reversible ischemia and myocardial viability should be considered to guide revascularization of patients with chronic ischemic LV dysfunction (Montalescot et al. 2013). Patients who have viable but ischemic myocardium are at higher risk if they are not revascularized, while the prognosis of patients without dysfunctional and viable myocardium is not improved by revascularization. Several observational studies have shown that the presence of ischemic but viable myocardium is associated with improved outcome after revascularization as compared with pharmacological therapy alone in patients with systolic LV dysfunction due to ischemic heart disease (Allman et al. 2002; Ling et al. 2013). Evaluation of residual glucose metabolism, a hallmark of viable myocardium, by 18F-2-fluoro-2-deoxyglucose (FDG) PET is considered as the most sensitive noninvasive tool to assess myocardial viability (Schinkel et al. 2007). A hybrid PET-CT scanner permits evaluation of viability with FDG-PET immediately in combination with coronary anatomy by CTA and automatic fusion of FDG images with coronary images, but the incremental value of using hybrid PET-CTA imaging in ischemic heart failure remains largely to be studied. It is also worth mentioning that rapid HR and renal dysfunction are common in heart failure and may often preclude the use of contrast-enhanced CTA.
Cationic Sensitizers, Combination Therapies, and New Methodologies
Published in Barbara W. Henderson, Thomas J. Dougherty, Photodynamic Therapy, 2020
Although augmentation of glycolysis through glucose administration can cause increased uptake of PII and thereby enhance phototoxicity [56], inhibition of glycolysis can also be effective. As noted above, both CPS and at least some APS including PII can cause mitochondrial damage, blocking respiration, and decreasing intracellular ATP [35,41,42,46,57]. Interference with glycolysis by 2-deoxyglucose (2-DG) [6], or other agents such as lonidamine [58–61], will further deplete ATP and contribute to cellular injury. In addition, irrespective of the extent of direct cellular injury, blocking anaerobic metabolism should contribute to killing of the cells at the margins of hypoxic zones caused by PDT-induced vascular shutdown.
Recent advances in PET probes for hepatocellular carcinoma characterization
Published in Expert Review of Medical Devices, 2019
Luca Filippi, Orazio Schillaci, Oreste Bagni
PET with FDG is a well-established imaging modality for diagnosis, staging, and monitoring the response to treatments in the majority of cancers [22]. Nevertheless, FDG PET is of limited value for the detection and characterization of HCC with reported sensitivity of about 52%. This low value is likely due to the high dephosphorylation rate of 2-deoxyglucose-6-phosphate by glucose-6-phosphatase (G6Pase), a gluconeogenesis enzyme strongly expressed in the liver and in the well-differentiated HCC, converting glucose-6-phosphate to glucose and consequently causing reduced retention of FDG within the tumoral cells [23]. The molecular mechanisms underlying the uptake of FDG in hepatic tumors versus metastases have been elucidated by Izuishi and colleagues analyzing 34 patients (14 Meta and 20 HCC) who underwent FDG-PET and hepatectomy [24]. In these subjects, PET sensitivity was lower in HCC (15/20) compared to metastases (13/14) as well as HK and GLUT expression were lower and G6Pase expression was higher in HCC compared to secondary lesions.
Biochanin A prevents 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced adipocyte dysfunction in cultured 3T3-L1 cells
Published in Journal of Environmental Science and Health, Part A, 2019
Eun Mi Choi, Kwang Sik Suh, So Young Park, Sang Ouk Chin, Sang Youl Rhee, Suk Chon
Glucose uptake by differentiated 3T3-Ll cells was measured using a Glucose Uptake Colorimetric Assay Kit (BioVision, Inc., Milpitas, CA, USA). Among the many different methods available for measuring glucose uptake, 2-deoxyglucose (2-DG) has been widely used because of its structural similarity to glucose. As with glucose, 2-DG is taken up by glucose transporters and metabolized to 2-DG-6-phosphate (2-DG6P). However, 2-DG6P cannot be further metabolized, and thus accumulates in cells. The amount of accumulated 2-DG6P is directly proportional to 2-DG (or glucose) uptake by cells. In this assay kit, 2-DG6P is oxidized to generate nicotinamide adenine dinucleotide phosphate (NADPH), which can be determined by an enzymatic recycling amplification reaction. Briefly, cells were grown and differentiated in 96-well culture plates. To assay glucose uptake, the adipocytes were washed twice with PBS and starved in 100 µL serum free adipocyte medium overnight (to increase glucose uptake), and then rewashed with PBS. The cells were glucose-starved by preincubating them with 100 µL Krebs-Ringer-phosphate-4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer containing 2% bovine serum albumin for 40 min and then stimulated with 100 nM insulin for 20 min to activate the glucose transporter. The cells were incubated with 10 µL of 10 mM 2-DG for 20 min. The cells then were washed with PBS to remove exogenous 2-DG. To degrade endogenous NAD(P) and denature the enzymes, the cells were lysed with 80 μL of extraction buffer, freeze/thawed once, and heated at 85 °C for 40 min. The cell lysate was cooled on ice for 5 min and neutralized by adding 10 μL of neutralization buffer. After brief centrifugation and dilution, the supernatant was added to a 96-well plate. A 10 µL aliquot of Reaction Mix A (BD Biosciences, San Jose, CA, USA) was added to each well and incubated at 37 °C for 1 h. To degrade the unused NADP, 90 µL of extraction buffer was added to each well. After sealing with aluminum sealing tape and heating to 90 °C for 40 min, the solution was cooled on ice for 5 min. A 12 µL aliquot of neutralization buffer was added, 38 µL of Reaction Mix B (BD Biosciences) was added, and absorbance was measured at 412 nm in a microplate reader.