Enhancement of cytotoxicity of artemisinins toward cancer cells by ferrous iron
Enhancement of cytotoxicity of artemisinins toward cancer cells by ferrous iron
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DOI：
10.1016/j.freeradbiomed.2004.06.023
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发表时间：
2004-10-01
影响因子：
7.4
通讯作者：
Marschall, M
中科院分区：
文献类型：
--
作者：
Efferth, T;Benakis, A;Marschall, M
铁(II)-血红素介导的青蒿素过氧化键的激活被认为产生了负责其抗疟疾活性的自由基氧物种。我们分析了亚铁在青蒿素对肿瘤细胞毒性中的作用。与不加铁的青蒿素相比，甘氨酸铁和转铁蛋白可使游离青蒿琥酯、微囊化青蒿琥酯和青蒿素对CCRF-CEM白血病细胞和U373星形细胞瘤细胞的细胞毒作用增强1.5~10.3倍。青蒿琥酯和亚铁抑制细胞生长与诱导细胞凋亡有关。未观察到青蒿琥酯和亚铁对细胞周期的干扰。对p53野生型TK6和突变的WTK1淋巴母细胞的处理表明，抑癌基因p53的突变状态并不影响青蒿琥酯的敏感性。铁和转铁蛋白的作用可被与转铁蛋白竞争结合的转铁蛋白受体(TFR)单抗RVS10逆转。CCRF-CEM和U373细胞分别有95%和48%的细胞表达TFR，而4例健康献血者外周血单个核细胞TFR的表达仅为0.4%~1.3%。这表明青蒿素加亚铁对肿瘤细胞的影响可能比正常细胞更大。通过Kendall‘s tau检验，在美国国家癌症研究所的60个细胞系中，一系列8种不同青蒿素衍生物的IC50值与参与铁吸收和代谢的12个基因的微阵列mRNA表达相关联，以确定提高青蒿素活性的铁响应细胞因子。这指向线粒体乌头酸酶和铜蓝蛋白(亚铁氧基酶)。(C)2004 Elsevier Inc.保留所有权利。
Iron(II) heme-mediated activation of the peroxide bond of artemisinins is thought to generate the radical oxygen species responsible for their antimalarial activity. We analyzed the role of ferrous iron in the cytotoxicity of artemisinins toward tumor cells. Iron(II)-glycine sulfate (Ferrosanol) and transferrin increased the cytotoxicity of free artesunate, artesunate microencapsulated in maltosyl-beta-cyclodextrin, and artemisinin toward CCRF-CEM leukemia and U373 astrocytoma cells 1.5- to 10.3-fold compared with that of artemisinins applied without iron. Growth inhibition by artesunate and ferrous iron correlated with induction of apoptosis. Cell cycle perturbations by artesunate and ferrous iron were not observed. Treatment of p53 wild-type TK6 and p53 mutated WTK1 lymphoblastic cells showed that mutational status of the tumor suppressor p53 did not influence sensitivity to artesunate. The effect of ferrous iron and transferrin was reversed by monoclonal antibody RVS10 against the transferrin receptor (TfR), which competes with transferrin for binding to TfR. CCRF-CEM and U373 cells expressed TfR in 95 and 48% of the cell population, respectively, whereas TfR expression in peripheral mononuclear blood cells of four healthy donors was confined to 0.4-1.3%. This indicates that artemisinins plus ferrous iron may affect tumor cells more than normal cells. The IC50 values for a series of eight different artemisinin derivatives in 60 cell lines of the U.S. National Cancer Institute were correlated with the microarray mRNA expression of 12 genes involved in iron uptake and metabolism by Kendall's tau test to identify iron-responsive cellular factors enhancing the activity of artemisinins. This pointed to mitochondrial aconitase and ceruloplasmin (ferroxidase). (C) 2004 Elsevier Inc. All rights reserved.