title: Combination treatment of glioblastoma multiforme cell lines with the anti-malarial artesunate and the epidermal growth factor receptor tyrosine kinase inhibitor OSI-774.
abstract: New drugs and combination modalities for otherwise non-responsive brain tumors are urgently required. The anti-malarial artesunate (ART) and the EGFR tyrosine kinase inhibitor OSI-774 reveal profound cytotoxic activity. The effectiveness of a combination treatment and the underlying molecular determinants of cellular response are unknown. In the present investigation, we studied ART and OSI-774 in glioblastoma multiforme (GBM) cell lines. Supra-additive inhibition of cell growth was observed in U-87MG.DeltaEGFR cells transduced with a deletion-mutant constitutively active EGFR gene, while additive effects were present in cells transduced with wild-type EGFR (U-87MG.WT-2N), kinase-deficient EGFR (U-87MG.DK-2N), mock vector controls (U-87MG.LUX), or non-transduced parental U-87MG cells. Among nine other non-transduced GBM cell lines, supra-additive effects were found in two cell lines (G-210GM, G-599GM), while ART and OSI-774 acted in an additive manner in the other seven cell lines (G-211GM, G-750GM, G-1163GM, G-1187GM, G-1265GM, G-1301GM, and G-1408GM). Sub-additive or antagonistic effects were not observed. Genomic gains and losses of genetic material in the non-transduced cell lines as assessed by comparative genomic hybridization were correlated with the IC(50) values for ART and OSI-774 and subsequently subjected to hierarchical cluster analysis and cluster image mapping. A genomic profile of imbalances was detected that predicted cellular response to ART and OSI-774. The genes located at the genomic imbalances of interest may serve as candidate resistance genes of GBM cells towards ART and OSI-774. In conclusion, the combination treatment of ART and OSI-774 resulted in an increased growth inhibition of GBM cell lines as compared to each drug alone.
authors.affiliation: Center for Molecular Biology, University of Heidelberg, Im Neuenheimer Feld 282, Heidelberg 69120, Germany. thomas.efferth@web.de
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
authors.forename: Tzutzuy
authors.initials: T
authors.lastname: Ramirez
authors.forename: Erich
authors.initials: E
authors.lastname: Gebhart
authors.forename: Marc-Eric
authors.initials: ME
authors.lastname: Halatsch
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols; D037621:Artemisinins / Q000494:pharmacology*; D000077332:Artesunate; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D016000:Cluster Analysis; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D005909:Glioblastoma / Q000473:pathology; D006801:Humans; D009693:Nucleic Acid Hybridization; D011799:Quinazolines / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D037621:Artemisinins; D011799:Quinazolines; D012717:Sesquiterpenes; D000077332:Artesunate; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors