Effects of deferasirox and deferiprone on cellular iron load in the human hepatoma cell line HepaRG |
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Authors: | François Gaboriau Anne-Marie Leray Martine Ropert Lucie Gouffier Isabelle Cannie Marie-Bérengère Troadec Olivier Loréal Pierre Brissot Gérard Lescoat |
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Institution: | 1.Inserm U991 (EA/MDC), Université de Rennes 1,H?pital Pontchaillou,Rennes Cedex,France;2.Laboratoire de Biochimie Générale et Enzymologie,H?pital Pontchaillou,Rennes,France;3.Service des Maladies du Foie,H?pital Pontchaillou,Rennes,France |
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Abstract: | Two oral chelators, CP20 (deferiprone) and ICL670 (deferasirox), have been synthesized for the purpose of treating iron overload
diseases, especially thalassemias. Given their antiproliferative effects resulting from the essential role played by iron
in cell processes, such compounds might also be useful as anticancer agents. In the present study, we tested the impact of
these two iron chelators on iron metabolism, in the HepaRG cell line which allowed us to study proliferating and differentiated
hepatocytes. ICL670 uptake was greater than the CP20 uptake. The iron depletion induced by ICL670 in differentiated cells
increased soluble transferrin receptor expression, decreased intracellular ferritin expression, inhibited 55Fe (III) uptake, and reduced the hepatocyte concentration of the labile iron pool. In contrast, CP20 induced an unexpected
slight increase in intracellular ferritin, which was amplified by iron-treated chelator exposure. CP20 also promoted Fe(III)
uptake in differentiated HepaRG cells, thus leading to an increase of both the labile pool and storage forms of iron evaluated
by calcein fluorescence and Perls staining, respectively. In acellular conditions, compared to CP20, iron removing ability
from the calcein-Fe(III) complex was 40 times higher for ICL670. On the whole, biological responses of HepaRG cells to ICL670
treatment were characteristic of expected iron depletion. In contrast, the effects of CP20 suggest the potential involvement
of this compound in the iron uptake from the external medium into the hepatocytes from the HepaRG cell line, therefore acting
like a siderophore in this cell model. |
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