New derivatives of 2-deoxy-D-glucose (2-DG) in the therapy of glioblastoma multiforme - preliminary studies

Q4 Biochemistry, Genetics and Molecular Biology

Journal of Cellular Neuroscience and Oxidative Stress Pub Date : 2019-06-21 DOI:10.37212/JCNOS.584722

E. Siwiak, M. Sołtyka

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引用次数: 0

Abstract

Tumor cells preferentially use the glycolysis process as a source of ATP regardless of the availability of oxygen (Warburg effect). GBM cells are particularly dependent on this process. A PET diagnostic test using a fluoro-labeled 2-DG derivative indicates that GBM cells accumulate 2-DG in their interior. Unfortunately, therapeutic use of 2-DG is limited due to insufficient pharmacokinetic parameters of the compound. However, a chemical modification involving the substitution of -OH groups with acetyl groups leads to an increase in 2-DG permeability across the BBB and its concentrations in GBM cells. Based on previous preliminary results using the O-acetylated 2-DG-2deoxy-3,6-di-O-acetyl-D-glucose derivative (WP1122), we assume that the new halogen (2-BG, 2-IG, 2-CG) and acetyl 2-DG derivatives will be highly cytotoxic to GBM cells. In addition, we anticipate the analysis of a new class of 2-DG derivatives, which may be modulated with ethylbutyrate and VPA, may also modulate the activity of HDAC and thus the expression of genes involved in cell apoptosis. The obtained preliminary results on the in vitro model showed that 2-DG decreases the viability of the U87 and U251 cell lines depending on the dose. The IC50 2-DG is for the following lines: U87-0.6mM, 0.5 mM (46,72h), U251-0.7mM, 0.45mM (48,72h). The percentage of apoptotic cells was evaluated by flow cytometry and cell staining with annexinV and PI. The MTT analysis of WP122 showed that the IC50 is in the cells of U87 line-1.5mM, 0.8mM (48,72h), U2511.25mM, 0.8mM (48,72h). The MTT analyzes of the effects of HDIs: NaBt and VPA determined the IC50 for NaBt: U87-1.48mM, 0.95mM (48,72h), U251-2.1mM, 2mM (48,72h); for VPA: U87-6.2mM, 6.0mM (48,72h), U251-5.3mM, 4.2mM (48,72h). Preliminary studies in the analysis of halo-derivatives interaction with hexokinase allowed to develop a model of expression and obtain a recombinant hexokinase protein, which will then be used for crystallographic analyzes.

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2-脱氧-D-葡萄糖新衍生物治疗多形性胶质母细胞瘤的初步研究

肿瘤细胞优先使用糖酵解过程作为ATP的来源，而不考虑氧气的可用性（Warburg效应）。GBM细胞特别依赖于这个过程。使用荧光标记的2-DG衍生物的PET诊断测试表明GBM细胞在其内部积聚2-DG。不幸的是，由于化合物的药代动力学参数不足，2-DG的治疗用途受到限制。然而，涉及用乙酰基取代-OH基团的化学修饰导致2-DG在血脑屏障中的渗透性及其在GBM细胞中的浓度增加。基于先前使用O-乙酰化的2-DG-2脱氧-3,6-二-O-乙酰基-D-葡萄糖衍生物（WP1122）的初步结果，我们假设新的卤素（2-BG，2-IG，2-CG）和乙酰基2-DG衍生物将对GBM细胞具有高度细胞毒性。此外，我们预计一类新的2-DG衍生物的分析，其可能被丁酸乙酯和VPA调节，也可能调节HDAC的活性，从而调节参与细胞凋亡的基因的表达。在体外模型上获得的初步结果表明，2-DG根据剂量降低U87和U251细胞系的活力。IC50 2-DG适用于以下生产线：U87-0.6mM、0.5mM（46,72h）、U251-0.7mM、0.45mM（48,72h）。通过流式细胞术和annexinV和PI的细胞染色来评估凋亡细胞的百分比。WP122的MTT分析显示，IC50在U87细胞系-1.5mM，0.8mM（48，72小时），U2511.25mM，0.8mM（48，78小时）中。MTT法分析HDIs的影响：NaBt和VPA测定了NaBt的IC50：U87-1.48mM，0.95mM（48,72h），U251-2.1mM，2mM（487,2h）；对于VPA:U87-6.2mM，6.0mM（48,72h），U251-5.3mM，4.2mM（48.72h）。在分析卤素衍生物与己糖激酶相互作用的初步研究中，开发了一种表达模型并获得了重组己糖激酶蛋白，然后将其用于晶体分析。

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来源期刊

Journal of Cellular Neuroscience and Oxidative Stress Biochemistry, Genetics and Molecular Biology-Biophysics

CiteScore

1.10

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0.00%

发文量

期刊介绍： Journal of Cellular Neuroscience and Oxidative Stress isan online journal that publishes original research articles, reviews and short reviews on themolecular basisofbiophysical,physiological and pharmacological processes thatregulate cellular function, and the control or alteration of these processesby theaction of receptors, neurotransmitters, second messengers, cation, anions,drugsor disease. Areas of particular interest are four topics. They are; 1. Ion Channels (Na+-K+Channels, Cl– channels, Ca2+channels, ADP-Ribose and metabolism of NAD+,Patch-Clamp applications) 2. Oxidative Stress (Antioxidant vitamins, antioxidant enzymes, metabolism of nitric oxide, oxidative stress, biophysics, biochemistry and physiology of free oxygen radicals) 3. Interaction Between Oxidative Stress and Ion Channels in Neuroscience (Effects of the oxidative stress on the activation of the voltage sensitive cation channels, effect of ADP-Ribose and NAD+ on activation of the cation channels which are sensitive to voltage, effect of the oxidative stress on activation of the TRP channels in neurodegenerative diseases such Parkinson’s and Alzheimer’s diseases) 4. Gene and Oxidative Stress (Gene abnormalities. Interaction between gene and free radicals. Gene anomalies and iron. Role of radiation and cancer on gene polymorphism)