Effects of deferasirox and deferiprone on cellular iron load in the human hepatoma cell line HepaRG
Effects of deferasirox and deferiprone on cellular iron load in the human hepatoma cell line HepaRG
复制标题
DOI：
10.1007/s10534-009-9281-9
复制
发表时间：
2010-04-01
期刊：
影响因子：
3.5
通讯作者：
Lescoat, Gerard
中科院分区：
文献类型：
--
作者：
Gaboriau, Francois;Leray, Anne-Marie;Lescoat, Gerard
已经合成了两种口服螯合剂CP20（去铁素）和ICL670（去铁素），用于治疗铁超载疾病，特别是地中海贫血。考虑到铁在细胞过程中所起的重要作用所产生的抗增殖作用，这些化合物也可能是有用的抗癌剂。在本研究中，我们在HepaRG细胞系中测试了这两种铁螯合剂对铁代谢的影响，从而使我们能够研究增殖和分化的肝细胞。ICL670的摄取大于CP20的摄取。ICL670在分化细胞中诱导的铁消耗增加了可溶性转铁蛋白受体的表达，降低了细胞内铁蛋白的表达，抑制了Fe-55 （III）的摄取，降低了肝细胞不稳定铁池的浓度。相比之下，CP20诱导细胞内铁蛋白的意外轻微增加，这被铁处理的螯合剂暴露放大。CP20还促进分化的HepaRG细胞对Fe（III）的摄取，从而导致钙黄蛋白荧光和Perls染色分别评估的铁的不稳定池和储存形式增加。在非细胞条件下，与CP20相比，ICL670从钙黄蛋白-铁（III）复合物中去除铁的能力高40倍。总体而言，HepaRG细胞对ICL670处理的生物学反应具有预期铁耗尽的特征。相比之下，CP20的作用表明，该化合物可能参与了从外部培养基到HepaRG细胞系的肝细胞的铁摄取，因此在该细胞模型中起着铁载体的作用。
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 Fe-55 (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.