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Darmstadt, Germany

Struh C.M.,Albert Ludwigs University of Freiburg | Struh C.M.,Carl Gustav Carus Institute | Jager S.,Betulin Institute | Jager S.,Birken AG | And 6 more authors.

Purpose:Mistletoe extracts are often used in complementary cancer therapy although the efficacy of that therapy is controversially discussed. Approved mistletoe extracts contain mainly water soluble compounds of the mistletoe plant, i.e. mistletoe lectins. However, mistletoe also contains water-insoluble triterpenoids (mainly oleanolic acid) that have anti-tumorigenic effects. To overcome their loss in watery extracts we have solubilized mistletoe triterpenoids with cyclodextrins, thus making them available for in vivo cancer experiments.Experimental design:B16.F10 subcutaneous melanoma bearing C57BL/6 mice were treated with new mistletoe extracts containing both water soluble compounds and solubilized triterpenoids. Tumor growth and survival was monitored. In addition, histological examinations of the tumor material and tumor surrounding tissue were performed.Results:Addition of solubilized triterpenoids increased the anti-tumor effects of the mistletoe extracts, resulting in reduced tumor growth and prolonged survival of the mice. Histological examination of the treated tumors showed mainly tumor necrosis and some apoptotic cells with active caspase-3 and TUNEL staining. A significant decrease of CD31-positive tumor blood vessels was observed after treatment with solubilized triterpenoids and different mistletoe extracts.Conclusion:We conclude that the addition of solubilized mistletoe triterpenoids to conventional mistletoe extracts improves the efficacy of mistletoe treatment and may represent a novel treatment option for malignant melanoma. © 2013 Strüh et al. Source

Weckesser S.,Albert Ludwigs University of Freiburg | Laszczyk M.N.,Betulin Institute | Muller M.L.,Albert Ludwigs University of Freiburg | Schempp C.M.,Albert Ludwigs University of Freiburg | And 2 more authors.
Forschende Komplementarmedizin

Betulin, a pentacyclic triterpene, is the main constituent of the outer bark of birches (Betula alba). In recent years, anti-microbial, anti-inflammatory and differentiation-promoting effects of betulin have been described. A betulinbased emulsion without preservatives and detergent emulsifiers can be prepared from birch bark extract. We report the successful treatment with betulin emulsion of a severe necrotising herpes zoster in an immunosuppressed patient who had not responded to a conventional topical treatment. The betulin emulsion was directly applied to the wounds without causing any side effects. The presented case report demonstrates impressive skin tolerance and wound-healing properties of the betulin emulsion. These should be further evaluated. © 2010 S. Karger AG, Basel. Source

Delebinski C.I.,Universitaetsmedizin Berlin | Jaeger S.,Birken AG | Jaeger S.,Betulin Institute | Kemnitz-Hassanin K.,Universitaetsmedizin Berlin | And 3 more authors.
Cell Proliferation

Objectives: Aqueous Viscum album L. extracts are widely used for anti-cancer therapies. Due to their low solubility, triterpenes (which are known to act on cancers), do not occur in aqueous extracts in significant amounts. Using cyclodextrins, we have found it possible to solubilize mistletoe triterpene acids and to determine their effects on acute lymphoblastic leukaemia (ALL) in vitro and in vivo. Materials and methods: A C.B-17/SCID model of pre-B ALL (NALM-6) was used to test efficacy and mechanisms of treatment with lectin- and triterpene acid containing preparations in vivo. Cytotoxicity of increasing concentrations of V. album L. preparations was assessed in vitro. Apoptosis was determined using mitochondrial membrane potential measurements, annexin V/PI, western blot analyses and caspase inhibitor assays. Results: Solubilized triterpene acid- or lectin-containing V. album L. extracts inhibited cell proliferation and demonstrated cytotoxic properties in vitro. Annexin V/PI and mitochondrial membrane potential assays indicated that dose-dependent induction of apoptosis was the main mechanism. Combination (viscumTT) of lectin- (viscum) and triterpene-containing (TT) extracts resulted in greatest induction of apoptosis. Furthermore, caspase activity demonstrated that these extracts were able to induce apoptosis through both caspase-8 and -9 dependent pathways. In vivo experimentation showed that treatment of mice with viscumTT combination prolonged mean survival to 50.5 days compared to 39.3days in the phosphate-buffered saline group. Conclusion: Here for the first time, we have demonstrated that either solubilized triterpene acids or lectins and combinations thereof, induce dose-dependent apoptosis in the ALL cell line NALM-6 via caspase-8 and -9 dependent pathways. © 2012 Blackwell Publishing Ltd. Source

Hertrampf A.,Albert Ludwigs University of Freiburg | Grundemann C.,Albert Ludwigs University of Freiburg | Jager S.,Birken AG | Jager S.,Betulin Institute | And 4 more authors.
Planta Medica

Triterpenoids from birch bark, like betulin, seem to have an anticancer potential which needs to be further investigated. Aim of this study was first to explore whether a cyclodextrin-solubilised triterpenoid extract (STE) from birch bark induces selective cytotoxic effects in primary liver cancer cells compared to healthy human hepatocytes. Second, selective cytotoxicity against several tumour cell lines should be analysed. For this purpose, human liver cancer cells derived from mouse xenografts (LIXF 575), healthy human hepatocytes, and 42 different human tumour cell lines were incubated with different concentrations of STE corresponding to 4.3 M - 137.5 M betulin (BE). Cytotoxicity was tested with the WST-1 cell proliferation assay, apoptosis with caspase 3/7-activity, and necrosis was determined by the propidiumiodid uptake assay. The pathway of cytotoxic effects was further investigated by immunoblotting of apoptosis inducing factor (AIF) and p53. The monolayer assay was used to analyse selectivity of STE towards different tumour cell lines. STE significantly (p < 0.001) reduced viability and induced apoptosis of LIXF cells in low concentrations corresponding to 8.6 M BE, while human hepatocytes were affected only in concentrations 68.8 M. Cell death occurred in a p53 independent manner, and AIF was not involved. The mean ICin the 42 tumour cell lines corresponded to 4.3 M BE and ranged from 2.05 M to 8.95 M BE content. Selectivity was, therefore, rather low. In conclusion, STE exhibits in low concentrations cytotoxicity in a broad spectrum of primary cancer cells and cancer cell lines, which is, at least in LIXF cells, induced by caspase 3/7 mediated apoptosis. STE is far less toxic in hepatocytes. The anticancer potential of STE should be further characterised and also investigated in animal models. © Georg Thieme Verlag KG Stuttgart · New York. Source

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