Abstract
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.
Highlights
Artemisinin is a sesquiterpene isolated from Artemisia annua L., which is used in traditional Chinese medicine for the treatment of fever and chills [1]
We focused on transferrin receptor (TfR), ABCB6, and ABCB7
We found that cell lines with high TfR expression significantly correlated with high degrees of modulation (Table 2) indicating that high TfR expressing tumor cells could be more efficiently inhibited by a combination of artesunate and iron(II) glycine sulfate than low TfR expressing ones
Summary
Artemisinin is a sesquiterpene isolated from Artemisia annua L., which is used in traditional Chinese medicine for the treatment of fever and chills [1]. Artesunate and artemether are semi-synthetic derivatives of artemisinin with improved pharmacological features [4] In addition to their antimalarial activity, artemisinin and its derivatives are active against cancer cells [5,6,7,8,9]. The active moiety of artemisinin-like drugs is an endoperoxide bridge, whose reductive homolysis is promoted by iron(II)-heme leading to C4-centered alkylating radicals [10]. These radical molecules cause macromolecular damage by alkylating essential malarial proteins inducing cell death of parasites [11,12,13]. We and others have shown that the susceptibility of tumor cells to artemisinins can further be enhanced by the addition of transferrin or ferrous iron [15,16]
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