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.

Synergistic Antitumour Properties ofviscumTTin Alveolar Rhabdomyosarcoma

“…MCL1, another antiapoptotic BCL2 family member, which is upregulated in RMS [ 77 ], is also downregulated by viscum and viscumTT . This is in line with the previous results of decreased expression of MCL1 after treatment with ML [ 21 , 78 ] and viscumTT [ 43 ]. Furthermore, Ryu et al have shown inhibition of the STAT3 pathway with downregulation of BCL2L1, BIRC5, and MCL1 after incubation with CDDO-Me [ 79 ].…”

“…OA treatment was able to effectively reduce BIRC5 expression in lung cancer [ 83 ], ovarian cell carcinoma [ 75 , 84 ], and leukaemia [ 76 ] as well as XIAP expression in hepatocellular carcinoma [ 85 ]. Furthermore, we were able to show that viscum , TT , and viscumTT led to downregulation of BIRC5 and XIAP in AML [ 41 ], Ewing-sarcoma [ 43 ], and osteosarcoma [ 44 ].…”

“…Previous studies showed the efficacy of a combined mistletoe extract produced by addition of solubilised triterpene acids ( TT ) to aqueous mistletoe extracts ( viscum ), creating a whole plant extract ( viscumTT ). This whole plant extract effectively induced apoptosis in acute myeloid and lymphoblastic leukaemia [ 41 , 42 ], Ewing-sarcoma [ 43 ], and osteosarcoma [ 44 ] and inhibited tumour growth in murine melanoma in vivo [ 45 ]. The aim of this study was to analyse the effect of the whole mistletoe extract, viscumTT , on rhabdomyosarcoma in vitro, ex vivo, and in vivo.…”

Identification of Viscum album L. miRNAs and prediction of their medicinal values

“…album extracts for this purpose are commercially available in Europe, such as Iscador ® , Eurixor ® , Helixor ® and Abnoba viscum ® . Three components of mistletoe, namely viscotoxins, lectins and terpenoids, which showed significant immune-system-stimulating activity and cell-killing activity, were suggested to be responsible for its anti-cancer effect [ 11 – 13 ]. In folk medicine, V .…”

Preventing and Mitigating Alcohol Toxicity: A Review on Protective Substances

“…Plant and fungi extracts that have been shown to help with alcohol degradation and toxicity include Viscum album L., Inonotus obliquus and Acanthopanax senticosus H. [139]. The main compounds extracted from these formulations that could be responsible for the protective actions are viscotoxins, flavonoids, triterpene acids, mistletoe lectins, melanins (lanoline alkane triterpenes), polyphenols, lignans, and coumarins, syringic acid, chlorogenic acid, eleutheroside, syringaresinol-di-glucoside, and isofraxidin [140][141][142][143]. The same composition in combination with Lycium chinense L., has also shown alcohol degradation, protection of the gastric mucous membrane, and reduction in nitric oxide and tumor necrosis factor production [139].…”