Molecular modes of action of artesunate in tumor cell lines

A profound cytotoxic action of the antimalarial, artesunate ( ART), was identified against 55 cancer cell lines of the U. S. National Cancer Institute (NCI). The 50% inhibition concentrations (IC50 values) for ART correlated significantly to the cell doubling times ( P = 0.00132) and the portion of cells in the G(0)/G(1) (P = 0.02244) or S cell cycle phases ( P = 0.03567). We selected mRNA expression data of 465 genes obtained by microarray hybridization from the NCI data base. These genes belong to different biological categories ( drug resistance genes, DNA damage response and repair genes, oncogenes and tumor suppressor genes, apoptosis-regulating genes, proliferation-associated genes, and cytokines and cytokine-associated genes). The constitutive expression of 54 of 465 (= 12%) genes correlated significantly to the IC50 values for ART. Hierarchical cluster analysis of these 12 genes allowed the differentiation of clusters with ART-sensitive or ART-resistant cell lines ( P = 0.00017). For exemplary validation, cell lines transduced with 3 of the 12 genes were used to prove a causative relationship. The cDNAs for a deletion-mutated epidermal growth factor receptor ( EGFR) and for gamma-glutamylcysteine synthetase increased resistance to ART. The conditional expression of the CDC25A gene using a tetracycline repressor expression vector increased sensitivity toward ART. Multidrug-resistant cells differentially expressing the MDR1, MRP1, or BCRP genes were not cross-resistant to ART. ART acts via p53-dependent and-independent pathways in isogenic p53 +/+ p21(WAF1/CIP1)+/+, p53 -/- p21(WAF1/CIP1) +/ +, and p53 +/ + p21(WAF1/CIP1) -/- colon carcinoma cells.