Molecular Modes of Action of Artesunate in Tumor Cell Lines

Abstract

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 ϭ 0.00132) and the portion of cells in the G 0 /G 1 (P ϭ 0.02244) or S cell cycle phases (P ϭ 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 (ϭ12%) 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 ϭ 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 andindependent pathways in isogenic p53ϩ/ϩ p21 WAF1/CIP1 ϩ/ϩ, p53Ϫ/Ϫ p21 WAF1/CIP1 ϩ/ϩ, and p53ϩ/ϩ p21 WAF1/CIP1

Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins

“…It is unknown yet, whether ARS derivatives belong to this category, as its prolonged use has not been reported. However, given its efficacy against drug-resistant tumor cells 17,19 and the relation to antiangiogenesis, it appears to be well-suited for adjuvant therapy in combination with classical chemotherapy. …”

“…14 The observation that ART inhibits the growth of many transformed cell lines has led to the hypothesis that the drug can also be useful for the treatment of human neoplasia. [15][16][17][18][19][20][21][22][23][24] As shown by us and others, [25][26][27][28][29][30][31][32] ARSs reveal antiangiogenic features in vitro and in vivo. The molecular determinants of the antiangiogenic activity of ARSs are incompletely understood at present.…”

Dihydroartemisinin Induces Apoptosis by a Bak-Dependent Intrinsic Pathway

“…Recent studies suggest a potential use of artemisinin and its active metabolite DHA as anticancer agents (6,(30)(31)(32). However, the molecular details of DHA-induced apoptosis remain unclear.…”

Gene expression profiling identifies novel key players involved in the cytotoxic effect of Artesunate on pancreatic cancer cells

“…Large clinical studies with malaria patients have shown that ART is well tolerated, with a few and insignificant side effects [8][9][10]. In addition to the well known anti-malarial activity of ART, recently a cytotoxic action of ART against cancer cell lines of different tumor types is identified [11][12][13][14][15][16]. Until now, the accepted antitumor mechanism is similar to the antimalarial mechanism; the artemisinin structure contains an endoperoxide bridge that reacts with an iron atom to form free radicals [17][18][19], which causes macromolecular damage and cell death [20].…”