Details

Autor(en) / Beteiligte

• Efferth, Thomas
• Sauerbrey, Axel
• Olbrich, Armin
• Gebhart, Erich
• Rauch, Pia
• Weber, H Oliver
• Hengstler, Jan G
• Halatsch, Marc-Eric
• Volm, Manfred
• Tew, Kenneth D
• Ross, Douglas D
• Funk, Jens Oliver

Titel

Molecular Modes of Action of Artesunate in Tumor Cell Lines

Ist Teil von

• Molecular pharmacology, 2003-08, Vol.64 (2), p.382-394

Ort / Verlag

United States: American Society for Pharmacology and Experimental Therapeutics

Erscheinungsjahr

2003

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 (IC 50 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 IC 50 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 γ-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.