Eltrombopag: a powerful chelator of cellular or extracellular iron(III) alone or combined with a second chelator.
Eltrombopag: a powerful chelator of cellular or extracellular iron(III) alone or combined with a second chelator.
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DOI：
10.1182/blood-2016-10-740241
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发表时间：
2017-10-26
期刊：
影响因子：
20.3
通讯作者：
Porter J
中科院分区：
文献类型：
--
作者：
Vlachodimitropoulou E;Chen YL;Garbowski M;Koonyosying P;Psaila B;Sola-Visner M;Cooper N;Hider R;Porter J
艾曲泊帕（ELT）是一种血小板生成素受体激动剂，据报道可降低白血病细胞中的不稳定铁。在这里，我们研究了以前未描述的铁（III）的协调和细胞铁动员ELT的属性。我们发现铁（III）的结合常数很高（log β2=35）。临床可达到的浓度（1 μM）可逐渐动员肝细胞、心肌细胞和胰腺细胞系的细胞铁，快速降低细胞内活性氧（ROS），并恢复胰腺细胞的胰岛素分泌。细胞铁蛋白的减少导致总细胞铁去除，特别是在肝细胞中。从心肌细胞铁动员超过了去铁酮，去铁胺，或地拉罗司在类似的铁结合当量。当与这些螯合剂组合时，ELT增强细胞铁动员超过与地拉罗司的加和（协同）。铁结合形态图与ELT在临床相关浓度下向地拉罗司提供铁一致。ELT比地拉罗司更快地清除柠檬酸铁物质，但迅速将螯合铁提供给地拉罗司，这与穿梭机制一致。穿梭也表明，当与其他无效的细胞外羟基吡啶酮螯合剂CP 40组合时，ELT增强了细胞铁动员。我们得出结论，ELT是一种强大的铁螯合剂，减少细胞铁，并进一步提高铁动员时，与临床上可用的螯合剂。
Eltrombopag (ELT) is a thrombopoietin receptor agonist reported to decrease labile iron in leukemia cells. Here we examine the previously undescribed iron(III)-coordinating and cellular iron-mobilizing properties of ELT. We find a high binding constant for iron(III) (log β2=35). Clinically achievable concentrations (1 μM) progressively mobilized cellular iron from hepatocyte, cardiomyocyte, and pancreatic cell lines, rapidly decreasing intracellular reactive oxygen species (ROS) and also restoring insulin secretion in pancreatic cells. Decrements in cellular ferritin paralleled total cellular iron removal, particularly in hepatocytes. Iron mobilization from cardiomyocytes exceeded that obtained with deferiprone, desferrioxamine, or deferasirox at similar iron-binding equivalents. When combined with these chelators, ELT enhanced cellular iron mobilization more than additive (synergistic) with deferasirox. Iron-binding speciation plots are consistent with ELT donating iron to deferasirox at clinically relevant concentrations. ELT scavenges iron citrate species faster than deferasirox, but rapidly donates the chelated iron to deferasirox, consistent with a shuttling mechanism. Shuttling is also suggested by enhanced cellular iron mobilization by ELT when combined with the otherwise ineffective extracellular hydroxypyridinone chelator, CP40. We conclude that ELT is a powerful iron chelator that decreases cellular iron and further enhances iron mobilization when combined with clinically available chelators.
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影响因子：
20.6
作者：
Alderighi, L;Gans, P;Vacca, A
通讯作者：
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影响因子：
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