5 years ago

Eltrombopag: a powerful chelator of cellular or extracellular iron(III) alone or combined with a second chelator.

Cooper N, Porter J, Sola-Visner M, Psaila B, Koonyosying P, Chen YL, Hider R, Garbowski M, Vlachodimitropoulou E
Eltrombopag (ELT) is a thrombopoietin receptor agonist, also 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 (1μM) progressively mobilised cellular iron from hepatocyte, cardiomyocyte and pancreatic cell lines, rapidly decreasing intracellular ROS and also restoring insulin secretion in pancreatic cells. Decrements in cellular ferritin paraleled total cellular iron removal, particularly in hepatocytes. Iron mobilisation from cardiomyocytes exceeded that obtained with deferiprone, desferrioxamine or deferasirox at similar iron-binding equivalents. When combined with these chelators, ELT enhanced cellular iron mobilisation, this being greater 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 mobilisation 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 mobilisation when combined with clinically available chelators.

Publisher URL: https://www.ncbi.nlm.nih.gov/pubmed/28864815

DOI: PubMed:28864815

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