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

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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.

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Most cited references 38

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Author and article information

Contributors

: Role: Academic Editor

Journal

Journal ID (nlm-ta): PLoS ONE

Journal ID (publisher-id): plos

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2007

Publication date (Electronic): 29 August 2007

Volume: 2

Issue: 8

Electronic Location Identifier: e798

Affiliations

[1 ]Oncotest GmbH, Institute of Experimental Oncology, Freiburg, Germany

[2 ]Department for Pediatrics, University of Ulm, Ulm, Germany

[3 ]Pharmaceutical Biology (C015), German Cancer Research Center, Heidelberg, Germany

[4 ]Department of Biotechnology, Kyoto Institute of Technology, Kyoto, Japan

Ordway Research Institute, United States of America

Author notes

* To whom correspondence should be addressed. E-mail: t.efferth@ 123456dkfz.de

Conceived and designed the experiments: HF. Performed the experiments: TT VK ST GK. Analyzed the data: HF. Wrote the paper: TE DS.

Article

Publisher ID: 07-PONE-RA-01326R1

DOI: 10.1371/journal.pone.0000798

PMC ID: 1949049

PubMed ID: 17726528

SO-VID: 12015c52-f2b5-4a88-b5cf-077639abcd4a

Copyright © Kelter et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 18 May 2007

Date accepted : 30 July 2007

Page count

Pages: 7

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