Reaction kinetics and targeting to cellular glutathione S-transferase of the glutathione peroxidase mimetic PhSeZnCl and its D,L-polylactide microparticle formulation.
Reaction kinetics and targeting to cellular glutathione S-transferase of the glutathione peroxidase mimetic PhSeZnCl and its D,L-polylactide microparticle formulation.
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DOI：
10.1016/j.freeradbiomed.2014.10.008
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发表时间：
2015-01
影响因子：
7.4
通讯作者：
Galli, F.
中科院分区：
文献类型：
--
作者：
Bartolini, D.;Piroddi, M.;Tidei, C.;Giovagnoli, S.;Pietrella, D.;Manevich, Y.;Tew, K. D.;Giustarini, D.;Rossi, R.;Townsend, D. M.;Santi, C.;Galli, F.
关键词：
谷胱甘肽过氧化物酶（GPx）模拟化合物PhSeZnCl或其d，l-丙交酯聚合物微胶囊化形式（M-PhSeZnCl）的催化性能和细胞效应进行了研究，并与原型硒有机化合物依布硒和二硒化物（PhSe）2进行了比较。PhSeZnCl被证实催化GPx的乒乓反应，具有比依布硒啉和（PhSe）2更高的Vmax，但计算的共底物谷胱甘肽（GSH）和H2 O2的催化效率，特别是对硫醇的高反应性（在一系列测试分子中GSH的最低KM），表明PhSeZnCl作为GPx模拟物的生物适用性差。PhSeZnCl的细胞毒性在各种癌细胞系中通过增加活性氧（ROS）的产生、细胞内硫醇的消耗和诱导细胞凋亡而得到证实。在谷胱甘肽S-转移酶P（GSTP）过表达K562人红白血病细胞和GSTP 1 -1敲除小鼠胚胎成纤维细胞（MEFs）中进行的实验表明，这种胞质酶代表了这种硒化合物产生的氧化还原紊乱的优先目标，在控制过氧化氢的产生和应激/生存激酶信号的扰动中起着关键作用。采用微胶囊化作为控制PhSeZnCl的硫醇反应性和氧化应激效应的策略，然后评估替代抗癌的应用。通过胞吞样机制发生的这种“去动力”GPx模拟制剂的摄取导致细胞毒性的显著降低。在MCF-7细胞转染不同的等位基因变体的GSTP，M-PhSeZnCl降低了细胞内的ROS的爆发暴露于细胞外H2 O2诱导，这种效果的程度之间的GSTP的变种。微胶囊化是一种简单的策略，以减轻毒性的巯基反应性硒有机药物，增强了抗氧化剂和细胞保护作用的PhSeZnCl。这些作用与GSTP的表达模式和信号传导特性的机制联系。这已经克服了GPx模拟范例提出的硒有机药物与更务实的概念GSTP信号调节剂。
Catalytic properties and cellular effects of the glutathione peroxidase (GPx)-mimetic compound PhSeZnCl or its d,l-lactide polymer microencapsulation form (M-PhSeZnCl) were investigated and compared with the prototypical Se-organic compounds ebselen and diselenide (PhSe)2. PhSeZnCl was confirmed to catalyze the ping-pong reaction of GPx with higher Vmax than ebselen and (PhSe)2, but the catalytic efficiency calculated for the cosubstrates glutathione (GSH) and H2O2, and particularly the high reactivity against thiols (lowest KM for GSH in the series of test molecules), suggested poor biological applicability of PhSeZnCl as a GPx mimetic. Cytotoxicity of PhSeZnCl was demonstrated in various cancer cell lines via increased reactive oxygen species (ROS) generation, depletion of intracellular thiols, and induction of apoptosis. Experiments carried out in GSH S-transferase P (GSTP)-overexpressing K562 human erythroleukemia cells and in GSTP1-1-knockout murine embryonic fibroblasts (MEFs) demonstrated that this cytosolic enzyme represents a preferential target of the redox disturbances produced by this Se-compound with a key role in controlling H2O2 generation and the perturbation of stress/survival kinase signaling. Microencapsulation was adopted as a strategy to control the thiol reactivity and oxidative stress effects of PhSeZnCl, then assessing applications alternative to anticancer. The uptake of this “depowered” GPx-mimetic formulation, which occurred through an endocytosis-like mechanism, resulted in a marked reduction of cytotoxicity. In MCF-7 cells transfected with different allelic variants of GSTP, M-PhSeZnCl lowered the burst of cellular ROS induced by the exposure to extracellular H2O2, and the extent of this effect changed between the GSTP variants. Microencapsulation is a straightforward strategy to mitigate the toxicity of thiol-reactive Se-organic drugs that enhanced the antioxidant and cellular protective effects of PhSeZnCl. A mechanistic linkage of these effects with the expression pattern and signaling properties of GSTP. This has overcome the GPx-mimetic paradigm proposed for Se-organic drugs with a more pragmatic concept of GSTP signaling modulators.
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影响因子：
7.4
作者：
Manevich, Y.;Hutchens, S.;Tew, K. D.;Townsend, D. M.
通讯作者：
Townsend, D. M.
影响因子：
15
作者：
Mugesh, G;Panda, A;Butcher, RJ
通讯作者：
Butcher, RJ
DOI：
10.1097/mco.0b013e3283139674
发表时间：
2008-11-01
影响因子：
3.1
作者：
Jackson, Matthew I.;Combs, Gerald F., Jr.
通讯作者：
Combs, Gerald F., Jr.
影响因子：
7.4
作者：
Betti, Michele;Minelli, Andrea;Galli, Francesco
通讯作者：
Galli, Francesco
影响因子：
2.8
作者：
Battistelli, Benedetta;Lorenzo, Testaferri;Santi, Claudio
通讯作者：
Santi, Claudio