title: Multiple Active Compounds from Viscum album L. Synergistically Converge to Promote Apoptosis in Ewing Sarcoma.
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.
authors: Department of Pediatric Oncology/Hematology, Otto Heubner Centre for Pediatric and Adolescent Medicine (OHC), Charité, Universitätsmedizin Berlin, Germany.|Institute of Pharmacy, Department of Biology, Chemistry, Pharmacy, Freie Universität, Berlin, Germany.
authors: Monika
authors: M
authors: Twardziok
authors: Department of Pediatric Oncology/Hematology, Otto Heubner Centre for Pediatric and Adolescent Medicine (OHC), Charité, Universitätsmedizin Berlin, Germany.
authors: Susann
authors: S
authors: Kleinsimon
authors: EPO GmbH, Experimental Pharmacology & Oncology, Berlin, Germany.
authors: Jana
authors: J
authors: Rolff
authors: Birken AG, Niefern-Öschelbronn, Germany.
authors: Sebastian
authors: S
authors: Jäger
authors: Department of Pediatric Oncology/Hematology, Otto Heubner Centre for Pediatric and Adolescent Medicine (OHC), Charité, Universitätsmedizin Berlin, Germany.
authors: Angelika
authors: A
authors: Eggert
authors: Department of Pediatric Oncology/Hematology, Otto Heubner Centre for Pediatric and Adolescent Medicine (OHC), Charité, Universitätsmedizin Berlin, Germany.
authors: Georg
authors: G
authors: Seifert
authors: Department of Pediatric Oncology/Hematology, Otto Heubner Centre for Pediatric and Adolescent Medicine (OHC), Charité, Universitätsmedizin Berlin, Germany.
authors: Catharina I
authors: CI
authors: Delebinski
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D008517:Phytotherapy / Q000379:methods; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome; D028182:Viscum album
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D010936:Plant Extracts; D053181:Caspase 8; D053453:Caspase 9