mRNA expression profiles for the response of human tumor cell lines to the antimalarial drugs artesunate, arteether, and artemether.

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.