Role of Transferrin Receptor and the ABC Transporters ABCB6 and ABCB7 for Resistance and Differentiation of Tumor Cells towards Artesunate

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.

ATP Binding Cassette transporters associated with chemoresistance: transcriptional profiling in extreme cohorts and their prognostic impact in a cohort of 281 acute myeloid leukemia patients

“…19 Like ABCB6, ABCC13 affects clinical response to neoadjuvant chemotherapy in breast cancer. 37 In the present study their expressions were strongly correlated.…”

“…36 Otherwise, ABCB6 was shown to be involved in resistance of tumor cells towards artesunate 37 and to be significantly overexpressed in melanoma cells, when compared to normal melanocytes.…”

Stem and progenitor cell-mediated tumor selective gene therapy

“…In antitumor approaches, for example, numerous constructs have been reported that target transferrin receptor, [39][40][41][42][43][44][45] since this receptor has been reported to be expressed at levels approximately twofold higher in tumors than in normal tissues. 46,47 Intuitively, a twofold difference may not provide a sufficient differential between tumor and normal tissue to confer tumor selectivity, unless the dose-response curve of the therapeutic entity is very steep.…”

Missense mutations in the ABCB6 transporter cause dominant familialpseudohyperkalemia

“…ABCB6 is a member of the B (MDR/TAP) subfamily of ABC transporters best known as drug-resistance genes, and it can form homodimers [19]. Indeed, increased ABCB6 expression correlates with increased drug resistance in multiple cell lines [34,35]. A specific ABCB6 function was first described in Saccharomyces cerevisiae mutants lacking mitochondrial ABC transporter Atm1p [36].…”