Koumoutsea, EV;
Garbowski, M;
Porter, J;
(2015)
Synergistic intracellular iron chelation combinations: mechanisms and conditions for optimizing iron mobilization.
British Journal of Haematology
, 170
(6)
pp. 874-883.
10.1111/bjh.13512.
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Abstract
Iron chelators are increasingly combined clinically but the optimal conditions for cellular iron mobilization and mechanisms of interaction are unclear. Speciation plots for iron(III) binding of paired combinations of the licensed iron chelators desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) suggest conditions under which chelators can combine as ‘shuttle’ and ‘sink’ molecules but this approach does not consider their relative access and interaction with cellular iron pools. To address this issue, a sensitive ferrozine‐based detection system for intracellular iron removal from the human hepatocyte cell line (HuH‐7) was developed. Antagonism, synergism or additivity with paired chelator combinations was distinguished using mathematical isobologram analysis over clinically relevant chelator concentrations. All combinations showed synergistic iron mobilization at 8 h with clinically achievable concentrations of sink and shuttle chelators. Greatest synergism was achieved by combining DFP with DFX, where about 60% of mobilized iron was attributable to synergistic interaction. These findings predict that the DFX dose required for a half‐maximum effect can be reduced by 3·8‐fold when only 1 μmol/l DFP is added. Mechanisms for the synergy are suggested by consideration of the iron‐chelate speciation plots together with the size, charge and lipid solubilities for each chelator. Hydroxypyridinones with low lipid solubilities but otherwise similar properties to DFP were used to interrogate the mechanistic interactions of chelator pairs. These studies confirm that synergistic cellular iron mobilization requires one chelator to have the physicochemical properties to enter cells, chelate intracellular iron and subsequently donate iron to a second ‘sink’ chelator.
| Type: | Article |
|---|---|
| Title: | Synergistic intracellular iron chelation combinations: mechanisms and conditions for optimizing iron mobilization |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/bjh.13512 |
| Publisher version: | https://doi.org/10.1111/bjh.13512 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | thalassaemia, iron overload, iron chelation, combination chelation therapy, isobologram |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10090310 |
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