The effect of the iron(III) chelator, desferrioxamine, on iron and transferrin uptake by the human malignant melanoma cell.
The effect of the iron(III) chelator, desferrioxamine, on iron and transferrin uptake by the human malignant melanoma cell.
复制标题
铁（III）螯合剂去铁胺对人恶性黑色素瘤细胞吸收铁和转铁蛋白的影响。
作者：
D. Richardson;P. Ponka;E. Baker
已使用人黑素瘤细胞系SK-MEL-28研究了临床上使用的铁（III）螯合剂去铁胺（DFO）防止铁（Fe）从转铁蛋白（Tf）摄取的作用机制。这项调查是由于缺乏信息的作用机制DFO在肿瘤细胞，因为最近的研究表明，DFO可能是一个有用的抗肿瘤剂。DFO的作用与孵育时间有关。孵育2小时后，DFO的作用类似于细胞外螯合剂EDTA和二乙烯三胺五乙酸，因为对Tf摄取59 Fe几乎没有抑制作用。相比之下，经过24小时的孵育，DFO（0.5 mM）有效地降低了从Tf的内化59 Fe摄取到对照值的18%。这些观察结果表明，存在一个动力学块的apochelator进入细胞内的铁池和/或退出的DFO-59 Fe复合物。事实上，细胞分馏表明，在铁蛋白和膜组分中的59 Fe的百分比的减少，在铁蛋白的细胞质中的59 Fe的百分比出现显着增加。这些观察结果表明DFO-59 Fe络合物在细胞内积累。高度亲脂性的铁螯合剂，吡哆醛异烟酰腙，是更有效的比DFO在防止59铁从Tf的吸收，说明膜渗透性的重要性，有效的铁螯合。浓度为1 mM的去铁胺使内化的125 I-Tf摄取降低至对照的70%。然而，观察到的59 Fe摄取的减少只能部分解释为Tf摄取的减少，并且DFO似乎在与转运Fe库一致的细胞内位点螯合59 Fe。结果进行了讨论的背景下使用的Fe螯合剂作为有效的螯合剂。
The mechanism of action of the clinically used iron(III) chelator, desferrioxamine (DFO), on preventing iron (Fe) uptake from transferrin (Tf) has been investigated using the human melanoma cell line SK-MEL-28. This investigation was initiated due to the paucity of information on the mechanisms of action of DFO in neoplastic cells and because recent studies have suggested that DFO may be a useful antitumor agent. The effect of DFO was dependent on incubation time. After a 2-h incubation, DFO acted like the extracellular chelators, EDTA and diethylenetriaminepentaacetic acid, because there was little inhibition of 59Fe uptake from Tf. In contrast, after a 24-h incubation, DFO (0.5 mM) efficiently reduced internalized 59Fe uptake from Tf to 18% of the control value. These observations suggested the existence of a kinetic block to the entry of the apochelator to intracellular Fe pools and/or to the exit of the DFO-59Fe complex. Indeed, cellular fractionation demonstrated that, in contrast to the decrease in the percentage of 59Fe in the ferritin and membrane fractions, a marked increase in the percentage of 59Fe present in the ferritin-free cytosol occurred. These observations suggested an accumulation of the DFO-59Fe complex within the cell. The highly lipophilic Fe chelator, pyridoxal isonicotinoyl hydrazone, was far more effective than DFO at preventing 59Fe uptake from Tf, illustrating the importance of membrane permeability for effective Fe chelation. Desferrioxamine at a concentration of 1 mM decreased internalized 125I-Tf uptake to 70% of the control. However, the decrease in 59Fe uptake observed could only be partially accounted for by a decrease in Tf uptake, and it appeared that DFO was chelating 59Fe at an intracellular site consistent with the transit Fe pool. The results are discussed in the context of the use of Fe chelators as effective antineoplastic agents.