title: Effects of TRAIL and taurolidine on apoptosis and proliferation in human             rhabdomyosarcoma, leiomyosarcoma and epithelioid cell sarcoma.
abstract: Soft tissue sarcomas (STS) are a heterogeneous group of malignant tumours representing 1% of all malignancies in adults. Therapy for STS should be individualised and multimodal, but complete surgical resection with clear margins remains the mainstay of therapy. Disseminated soft tissue sarcoma still represents a therapeutic dilemma. Commonly used chemotherapeutic agents such as doxorubicin and ifosfamide have proven to be effective in fewer than 30% in these cases. Therefore, we tested the apoptotic and anti-proliferative in vitro effects of TNF-related apoptosis-inducing ligand (TRAIL) and taurolidine (TRD) on rhabdomyosarcoma (A-204), leiomyosarcoma (SK-LMS-1) and epithelioid cell sarcoma (VA-ES-BJ) cell lines. Viability, apoptosis and necrosis were quantified by FACS analysis (propidium iodide/Annexin V staining). Gene expression was analysed by DNA microarrays and the results validated for selected genes by rtPCR. Protein level changes were documented by western blot analysis. Cell proliferation was analysed by BrdU ELISA assay. The single substances TRAIL and TRD significantly induced apoptotic cell death and decreased proliferation in rhabdomyosarcoma and epithelioid cell sarcoma cells. The combined use of TRAIL and TRD resulted in a synergistic apoptotic effect in all three cell lines, especially in rhabdomyosarcoma cells leaving 18% viable cells after 48 h of incubation (p<0.05). Analysis of the differentially regulated genes revealed that TRD and TRAIL influence apoptotic pathways, including the TNF-receptor associated and the mitochondrial pathway. Microarray analysis revealed remarkable expression changes in a variety of genes, which are involved in different apoptotic pathways and cross talk to other pathways at multiple levels. This in vitro study demonstrates that TRAIL and TRD synergise in inducing apoptosis and inhibiting proliferation in different human STS cell lines. Effects on gene expression differ relevantly in the sarcoma entities. These results provide experimental support for in vivo trials assessing the effect of TRAIL and TRD in STS and sustain the approach of individualized therapy.
authors: Department of Gynecology and Obstetrics, Marienhospital Witten,                     Ruhr-University, D-58452 Witten, Germany.
authors: C
authors: C
authors: Karlisch
authors: K
authors: K
authors: Harati
authors: A M
authors: AM
authors: Chromik
authors: D
authors: D
authors: Bulut
authors: L
authors: L
authors: Klein-Hitpass
authors: O
authors: O
authors: Goertz
authors: T
authors: T
authors: Hirsch
authors: M
authors: M
authors: Lehnhardt
authors: W
authors: W
authors: Uhl
authors: A
authors: A
authors: Daigeler
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D006801:Humans; D007890:Leiomyosarcoma / Q000188:drug therapy; D009687:Nuclear Proteins / Q000096:biosynthesis; D020411:Oligonucleotide Array Sequence Analysis; D054645:Protein Phosphatase 1 / Q000096:biosynthesis; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D012208:Rhabdomyosarcoma / Q000188:drug therapy; D012509:Sarcoma / Q000188:drug therapy*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D013654:Taurine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013829:Thiadiazines / Q000494:pharmacology*; D000097642:GADD45 Proteins
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D018840:HSP70 Heat-Shock Proteins; D009687:Nuclear Proteins; D054645:Protein Phosphatase 1; D011505:Protein-Tyrosine Kinases; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D013654:Taurine; D013829:Thiadiazines; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C525621:HSPA1B protein, human; C505653:TNFSF10 protein, human; C012566:taurolidine; C499349:WEE1 protein, human; C087519:PPP1R15A protein, human