期刊
BLOOD
卷 130, 期 17, 页码 1923-1933出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2016-10-740241
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资金
- Onassis Foundation, Athens, Greece
- Biomedical Research Centre, University College London
- Novartis
- Academy of Medical Sciences (AMS) [AMS-SGCL10-Psaila] Funding Source: researchfish
- European Hematology Association [TRTH100] Funding Source: researchfish
- National Institute for Health Research [CL-2012-21-004] Funding Source: researchfish
- Wellcome Trust [107477/Z/15/Z] Funding Source: researchfish
- Wellcome Trust [107477/Z/15/Z] Funding Source: Wellcome Trust
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 beta(2)=535). Clinically achievable concentrations (1 mu M) 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 other wise in effective 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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