title: Gene expression profiling identifies novel key players involved in the cytotoxic effect of Artesunate on pancreatic cancer cells.
abstract: Pancreatic cancer is one of the most aggressive human malignancies, with an extremely poor prognosis. The paucity of curative therapies has translated into an overall 5-year survival rate of less than 5%, underscoring a desperate need for new therapeutic options. Artesunate (ART), clinically used as anti-malarial agent, has recently revealed remarkable anti-tumor activity. However, the mechanisms underlying those activities in pancreatic cancer are not yet known. Here we evaluated the anti-tumor activity of Artesunate and the possible underlying mechanisms in pancreatic cancer. MiaPaCa-2 (poorly differentiated) and BxPC-3 (moderately differentiated) pancreatic cancer cell lines were treated with Artesunate and the effect was monitored by a tetrazolium-based assay (MTS) for evaluating cell viability and by flow cytometry and caspase 3/7 activation for apoptosis evaluation. In addition cDNA arrays were used to identify differentially expressed genes. The microarray data were then validated by RT-PCR and Western blotting. Moreover, pathways associated with these expression changes were identified using the Ingenuity Pathway Analysis. The expression analysis identified a common set of genes that were regulated by Artesunate in pancreatic cancer. Our results provide the first in vitro evidence for the therapeutic utility of Artesunate in pancreatic cancer. Moreover, we identified Artesunate as a novel topoisomerase IIalpha inhibitor that inhibits pancreatic cancer growth through modulation of multiple signaling pathways. 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 Artesunate in tumor cells.
authors.affiliation: Department of Functional Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany. m.youns@dkfz.de
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Youns
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
authors.forename: Jürgen
authors.initials: J
authors.lastname: Reichling
authors.forename: Kurt
authors.initials: K
authors.lastname: Fellenberg
authors.forename: Andrea
authors.initials: A
authors.lastname: Bauer
authors.forename: Jörg D
authors.initials: JD
authors.lastname: Hoheisel
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D037621:Artemisinins / Q000494:pharmacology*; D000077332:Artesunate; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D037621:Artemisinins; D000077332:Artesunate