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Molecular Modes of Action of Artesunate in Tumor Cell Lines

Center for Molecular Biology of the University of Heidelberg (ZMBH), Heidelberg, Germany (T.E.); Department of Pediatrics, University of Jena, Jena, Germany (A.S.); Hospital Pharmacy, University of Aachen, Aachen, Germany A.O.); Institute of Human Genetics (E.G.) and Laboratory of Molecular Tumor Biology, Department for Dermatology (P.R., H.O.W.), University of Erlangen-Nuremberg, Erlangen, Germany; Institute of Toxicology, University of Mainz, Mainz, Germany (J.G.H.); Department of Neurosurgery, University of Göttingen, Göttingen, Germany (M.-E.H.); German Cancer Research Center, Heidelberg, Germany (M.V.); Department of Pharmacology, Fox Chase Center, Philadelphia, Pennsylvania (K.D.T.); University of Maryland Greenebaum Cancer Center, Department of Medicine, University of Maryland School of Medicine, and the Baltimore Veterans Affairs Medical Center, Baltimore, Maryland (D.D.R.); and Department for Oncology Research, Merck KGaA, Darmstadt, Germany (J.O.F.)

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 G₀/G₁ (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 -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.

Address correspondence to: Thomas Efferth, Center for Molecular Biology of the University of Heidelberg (ZMBH), Heidelberg, Germany. E-mail: thomas.efferth{at}web.de

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