Abstract
BackgroundThe hydrophobic triterpenes, oleanolic and betulinic acid as well as the hydrophilic mistletoe lectins and viscotoxins possess anticancer properties. They do all occur in combination in European mistletoe (Viscum album L.). Commercial Viscum album L. extracts are aqueous, excluding the insoluble triterpenes. We have previously shown that mistletoe lectins and triterpene acids are effective against Ewing sarcoma in vitro, ex vivo and in vivo.MethodsWe recreated a total mistletoe effect (viscumTT) by combining an aqueous extract (viscum) and a triterpene extract (TT) solubilised with cyclodextrins and analysed the effects of viscumTT and the single extracts on TC-71 Ewing sarcoma cells in vitro by transcriptomic and proteomic profiling.ResultsTreatment with the extracts strongly impacted Ewing sarcoma cell gene and protein expression. Apoptosis-associated and stress-activated genes were upregulated, proteasomal protein abundance enhanced and ribosomal and spliceosomal proteins downregulated. The mechanism of action of viscum, TT and viscumTT in TC-71 and MHH-ES-1 cells suggests the involvement of the unfolded protein response. While viscum and viscumTT extract treatment indicate response to oxidative stress and activation of stress-mediated MAPK signalling, TT extract treatment suggests the involvement of TLR signalling and autophagy.ConclusionsSince the combinatory extract viscumTT exerts highly effective pro-apoptotic effects on Ewing sarcoma cells in vitro, this phytopolychemotherapy could be a promising adjuvant therapeutic option for paediatric patients with Ewing sarcoma.
Highlights
The hydrophobic triterpenes, oleanolic and betulinic acid as well as the hydrophilic mistletoe lectins and viscotoxins possess anticancer properties
AKT signalling has been implicated during mistletoe lectin or oleanolic acid treatment of gastric cancer, hepatocarcinoma, epidermoid cancer, colon carcinoma, ovarian cancer, prostate cancer, osteosarcoma and trophoblast cells, and oleanolic acid and its derivatives have been demonstrated to induce MTOR and NFKB1 signalling in prostate cancer, colon cancer and osteosarcoma cells [23, 26,27,28,29,30,31,32,33,34]
ViscumTT alters the transcriptomic profile Firstly, to explore global changes asserted by mistletoe extracts in the Ewing sarcoma cell transcriptome, we treated TC-71 cells for 24 h with viscum, triterpene extract (TT) or viscumTT in ~ IC50 concentrations in reference to untreated control cells and performed one mRNA sequencing experiment. mRNA sequencing detected >62,400 transcripts belonging to >17,300 genes
Summary
The hydrophobic triterpenes, oleanolic and betulinic acid as well as the hydrophilic mistletoe lectins and viscotoxins possess anticancer properties They do all occur in combination in European mistletoe (Viscum album L.). Mistletoe lectins and triterpene acids, such as betulinic acid or oleanolic acid and its derivatives, have been shown to inhibit cell growth and induce apoptosis in melanoma, breast cancer and leukaemia cells [16,17,18]. We have previously demonstrated the therapeutic effect of recombining hydrophilic and hydrophobic mistletoe constituents in the viscumTT extract for Ewing sarcoma (Twardziok et al, 2016, manuscript accepted 07/2016) and acute leukaemia cells in vitro and in vivo cancer models [35, 36]. The aim of the present study was to analyse the impact of viscumTT and the single extracts on the transcriptome and proteome of Ewing sarcoma cells and to further illuminate the involved signalling pathways
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