title: Effects of deferasirox and deferiprone on cellular iron load in the human hepatoma cell line HepaRG.
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 (55)Fe (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.
authors.affiliation: Inserm U991 (EA/MDC), Université de Rennes 1, Hôpital Pontchaillou, 35033 Rennes Cedex, France. francois.gaboriau@univ-rennes1.fr
authors.forename: François
authors.initials: F
authors.lastname: Gaboriau
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Leray
authors.forename: Martine
authors.initials: M
authors.lastname: Ropert
authors.forename: Lucie
authors.initials: L
authors.lastname: Gouffier
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cannie
authors.forename: Marie-Bérengère
authors.initials: MB
authors.lastname: Troadec
authors.forename: Olivier
authors.initials: O
authors.lastname: Loréal
authors.forename: Pierre
authors.initials: P
authors.lastname: Brissot
authors.forename: Gérard
authors.initials: G
authors.lastname: Lescoat
mesh_terms: D001565:Benzoates / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D000077588:Deferasirox; D000077543:Deferiprone; D004305:Dose-Response Relationship, Drug; D005260:Female; D005293:Ferritins / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008113:Liver Neoplasms / Q000378:metabolism*; D015394:Molecular Structure; D011728:Pyridones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011990:Receptors, Transferrin / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D001565:Benzoates; D007502:Iron Chelating Agents; D011728:Pyridones; D011990:Receptors, Transferrin; D014230:Triazoles; D000077543:Deferiprone; D005293:Ferritins; D007501:Iron; D000077588:Deferasirox