The
antimalarial artemisinin derivatives
artesunate (ART),
arteether (ARE), and
artemether (ARM) reveal remarkable
antineoplastic activity. In the present investigation, we identified
mRNA expression profiles associated with the response of
tumor cells to ART, ARE, and ARM. We performed correlation and hierarchical cluster analyses of inhibition concentration 50% (IC(50)) values and basal
mRNA expression levels of 464 genes deposited in the database of the National Cancer Institute, USA. Correlating IC(50) values of ART, ARE, and ARM and of 16 established
antineoplastic drugs revealed that the
artemisinin derivatives could not be assigned with a known class of drugs with defined mode(s) of action. The basal
mRNA expression of 208 out of 464 genes (45%) correlated significantly with IC(50) values of at least one
artemisinin derivative. These genes were from different classes (drug resistance genes, DNA damage and repair genes, apoptosis-regulating genes, proliferation-associated genes, oncogenes, tumor suppressor genes and
cytokines). We identified two different gene clusters by hierarchical cluster analysis. One cluster contained predominately genes significantly correlated to all three
artemisinin derivatives. This overlapping set of genes points to common molecular mechanisms of
tumor inhibition by all three drugs in which genes affecting cellular proliferation may play an important role. The second cluster contained genes differentially associated with the response of
artemisinin derivatives to
cancer cells. The number of correlating drug resistance genes in this cluster increased in the order ART<ARE<ARM and was paralleled by increasing IC(50) values of the three drugs in the same order. The higher activity of ART in comparison to ARE and ARM may, thus, be explained by a lower number of drug resistance genes affecting ARTs action. The present analysis is a starting point for the generation of hypotheses on candidate genes and for a more detailed dissection of the functional role of individual genes for the activity of
artemisinin derivatives in
tumor cells.