Abstract
Ewing sarcoma is the second most common bone cancer in children and adolescents, with poor prognosis and outcome in ~70% of initial diagnoses and 10–15% of relapses. Hydrophobic triterpene acids and hydrophilic lectins and viscotoxins from European mistletoe (Viscum album L.) demonstrate anticancer properties, but have not yet been investigated for Ewing sarcoma. Commercial Viscum album L. extracts are aqueous, excluding the insoluble triterpenes. We recreated a total mistletoe effect by combining an aqueous extract (viscum) and a triterpene extract (TT) solubilized with cyclodextrins. Ewing sarcoma cells were treated with viscum, TT and viscumTT in vitro, ex vivo and in vivo. In vitro and ex vivo treatment of Ewing sarcoma cells with viscum inhibited proliferation and induced apoptosis in a dose-dependent fashion, while viscumTT combination treatment generated a synergistic effect. Apoptosis occurred via intrinsic and extrinsic apoptotic pathways, evidenced by activation of both CASP8 and CASP9. We show that viscumTT treatment shifts the balance of apoptotic regulatory proteins towards apoptosis, mainly via CLSPN, MCL1, BIRC5 and XIAP downregulation. ViscumTT also demonstrated strong antitumor activity in a cell line- and patient-derived mouse model, and may be considered an adjuvant therapy option for pediatric patients with Ewing sarcoma.
Highlights
Ewing sarcoma, while the second most common bone sarcoma in children and adolescents, is rare and occurs in ~2.6 and ~2.8 per million children in the United States and Germany, respectively [1,2]
We flow cytometrically assessed the fraction of TC-71 and MHH-ES-1 cells undergoing apoptosis in response to 24h incubation with Viscum album L. extracts after annexin V/propidium iodide staining
Taken together, reconstituting Viscum album L. cytotoxic compounds in viscumTT had a synergistic and dose-dependent effect on proliferation and apoptosis in Ewing sarcoma cell lines
Summary
While the second most common bone sarcoma in children and adolescents (peaking in the second decade), is rare and occurs in ~2.6 and ~2.8 per million children in the United States and Germany, respectively [1,2]. It originates from either mesenchymal stem or neuronal crest cells [3,4]. Pathogenesis results from a balanced translocation of the EWS gene producing fusion proteins coding for chimeric transcription factors promoting cell growth.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
