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.