Role of transferrin receptor and the ABC transporters ABCB6 and ABCB7 for resistance and differentiation of tumor cells towards artesunate.
Role of transferrin receptor and the ABC transporters ABCB6 and ABCB7 for resistance and differentiation of tumor cells towards artesunate.
复制标题
DOI：
10.1371/journal.pone.0000798
复制
发表时间：
2007-08-29
期刊：
影响因子：
3.7
通讯作者：
Efferth T
中科院分区：
文献类型：
--
作者：
Kelter G;Steinbach D;Konkimalla VB;Tahara T;Taketani S;Fiebig HH;Efferth T
抗疟疾的青蒿琥酯还具有深刻的抗癌活性。亚铁可增强肿瘤细胞对青蒿琥酯的敏感性。转铁蛋白受体(TFR)通过转铁蛋白的内化参与铁的摄取，并在快速生长的肿瘤中过度表达。ATP结合盒(ABC)转运体ABCB6和ABCB7也参与了铁的动态平衡。为了研究这些蛋白质是否影响对青蒿琥酯的敏感性，Oncotest的36细胞系小组用青蒿琥酯或青蒿琥酯加甘氨酸硫酸铁(Ferosanol®)处理。与单独使用青蒿琥酯相比，青蒿琥酯与甘氨酸硫酸铁(II)联合使用时，大多数细胞株的抑制率增加。然而，在36个细胞系中，有11个细胞株的联合处理并不优越。高TFR表达的细胞系与高调控程度显着相关，表明这种联合治疗对高TFR表达的肿瘤细胞的抑制作用比低TFR表达的肿瘤细胞更有效。此外，我们在美国国家癌症研究所(NCI)的55个细胞系中发现了细胞对青蒿琥酯的反应与TFR表达之间的显著关系。在NCI小组中，ABCB6也发现了显著的相关性，但与ABCB7没有相关性。青蒿琥酯作用于人CCRF-CEM白血病细胞和MCF7乳腺癌细胞，诱导ABCB6表达，但抑制ABCB7表达。青蒿琥酯对小鼠红白血病细胞的增殖和分化有抑制作用。反义寡核苷酸下调ABCB6表达可抑制MEL细胞分化，提示青蒿琥酯与ABCB6可能具有协同作用。综上所述，我们的结果表明，亚铁可以改善某些肿瘤细胞系中青蒿琥酯的活性，但不是所有肿瘤细胞系。参与铁稳态的几个因素，如TFR和ABCB6，可能参与了这一效应。
The anti-malarial artesunate also exerts profound anti-cancer activity. The susceptibility of tumor cells to artesunate can be enhanced by ferrous iron. The transferrin receptor (TfR) is involved in iron uptake by internalization of transferrin and is over-expressed in rapidly growing tumors. The ATP-binding cassette (ABC) transporters ABCB6 and ABCB7 are also involved in iron homeostasis. To investigate whether these proteins play a role for sensitivity towards artesunate, Oncotest's 36 cell line panel was treated with artesunate or artesunate plus iron(II) glycine sulfate (Ferrosanol®). The majority of cell lines showed increased inhibition rates, for the combination of artesunate plus iron(II) glycine sulfate compared to artesunate alone. However, in 11 out of the 36 cell lines the combination treatment was not superior. Cell lines with high TfR expression significantly correlated with high degrees of modulation indicating that high TfR expressing tumor cells would be more efficiently inhibited by this combination treatment than low TfR expressing ones. Furthermore, we found a significant relationship between cellular response to artesunate and TfR expression in 55 cell lines of the National Cancer Institute (NCI), USA. A significant correlation was also found for ABCB6, but not for ABCB7 in the NCI panel. Artesunate treatment of human CCRF-CEM leukemia and MCF7 breast cancer cells induced ABCB6 expression but repressed ABCB7 expression. Finally, artesunate inhibited proliferation and differentiation of mouse erythroleukemia (MEL) cells. Down-regulation of ABCB6 by antisense oligonucleotides inhibited differentiation of MEL cells indicating that artesunate and ABCB6 may cooperate. In conclusion, our results indicate that ferrous iron improves the activity of artesunate in some but not all tumor cell lines. Several factors involved in iron homeostasis such as TfR and ABCB6 may contribute to this effect.
登录
查看更多内容
影响因子：
3.8
作者：
Park, Sarah;Shimizu, Chikako;Fujiwara, Yasuhiro
通讯作者：
Fujiwara, Yasuhiro
影响因子：
56.9
作者：
KLAYMAN, DL
通讯作者：
KLAYMAN, DL
影响因子：
9.7
作者：
Moore, JC;Lai, H;Chou, CK
通讯作者：
Chou, CK
影响因子：
7.4
作者：
Efferth, T;Benakis, A;Marschall, M
通讯作者：
Marschall, M
影响因子：
3.6
作者：
Efferth, T;Sauerbrey, A;Funk, JO
通讯作者：
Funk, JO