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.

Lipid Nanoparticles Decorated with TNF-Related Aptosis-Inducing Ligand (TRAIL) Are More Cytotoxic than Soluble Recombinant TRAIL in Sarcoma

“…It is interesting that in the several studies that have explored the anti-tumor potential of TRAIL in sarcomas, this death ligand has been used in combination with other drugs, indicating that some sarcoma types are partially resistant to the sTRAIL [ 27 , 28 , 33 , 35 , 36 , 37 ]. In this line, although LUV-TRAIL showed more pro-apoptotic potential than sTRAIL in sarcoma cell lines, they only induced a moderate cytotoxic effect in sTRAIL-resistant HT-1080 and RD cells.…”

Two-dimensional gel electrophoresis analysis of the leiomyoma interstitial fluid reveals altered protein expression with a possible involvement in pathogenesis

“…It is noteworthy that the anticancer protein TnF-related apoptosis inducing ligand (TRAIl) (32)(33) upregulates the HSP70 protein in the leiomyosarcoma cell line, thereby inducing apoptosis (34), which suggests that the increase of HSP70 may play a role in the anticancer response to TRAIl.…”

The Importance of Being Dead: Cell Death Mechanisms Assessment in Anti-Sarcoma Therapy

“…TRAIL is a death ligand that has been studied in several sarcomas for therapeutic purposes ( 79 – 81 ). TRAIL-induced apoptosis is regulated by other receptors and downstream effectors including cFLIP and the Bcl-2 family ( 82 – 84 ).…”