Molecular interactions of artemisinin with DNA and specific target proteins in cancer cells

The anti-malarial artemisinin from Artemisia annua L. also inhibits tumor cells in vitro and in vivo. Artemisinin induces apoptosis, but cellular upstream mechanisms are not understood. The susceptibility of tumor cells to artemisinin and its derivative, artesunate, was enhanced by ferrous iron. The transferrin receptor (TfR) transports iron and is overexpressed in tumors. The effect of ferrous iron on artesunate was reversed by monoclonal antibody RVS10, which competes with transferrin for TfR-binding [1]. The ATP-binding cassette transporter, ABCB6, is also involved in iron homeostasis. In 36 tumor cell lines, TfR and ABCB6 expression significantly correlated with the efficacy of artesunate and ferrous iron to inhibit growth. Down-regulation of ABCB6 by antisense oligodeoxynucleotides inhibited cellular differentiation and proliferation in MEL erythroleukemia cells [2]. Artesunate also induced DNA breakage as shown by Comet assay. Single strand breaks were repaired by base excision repair, double strand breaks by homologous repair and non-homologous end-joining [3]. By three-dimensional docking studies, the translationally controlled tumor protein (TCTP) was shown to bind artesunate at cysteine 124. This was verified by gene cloning the gene, protein expression and purification and mass spectrometry.

In conclusion, artemisinins form reactive radicals in the presence of ferrous iron. Adduct formation with DNA and specific target proteins contribute to their cytotoxicity.

References: 1. Efferth, et al. (2004) Free Rad. Biol. Med. 37:998–1009.

2. Efferth, et al. (2007) PLoS One 29:e798.

3. Li, et al. Cancer Research (in press).