Multiple Active Compounds from Viscum album L. Synergistically Converge to Promote Apoptosis in Ewing Sarcoma
Monika Twardziok, Susann Kleinsimon, Jana Rolff, Sebastian Jäger, Angelika Eggert, Georg Seifert, Catharina I Delebinski, Monika Twardziok, Susann Kleinsimon, Jana Rolff, Sebastian Jäger, Angelika Eggert, Georg Seifert, Catharina I Delebinski
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.
Conflict of interest statement
Competing Interests: The authors have the following interests: Jana Rolff is employed by EPO GmbH and Sebastian Jäger by Birken AG. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.
Figures
![Fig 1. ViscumTT inhibits proliferation in Ewing…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5010293/bin/pone.0159749.g001.jpg)
![Fig 2. ViscumTT combined extract synergistically induces…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5010293/bin/pone.0159749.g002.jpg)
![Fig 3. ViscumTT synergistically activates caspases in…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5010293/bin/pone.0159749.g003.jpg)
![Fig 4. Viscum, TT and viscumTT alter…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5010293/bin/pone.0159749.g004.jpg)
![Fig 5. ViscumTT and viscum induce apoptosis…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5010293/bin/pone.0159749.g005.jpg)
![Fig 6. ViscumTT reduces the growth of…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5010293/bin/pone.0159749.g006.jpg)
Fig 7. ViscumTT reduces the growth of…
Fig 7. ViscumTT reduces the growth of patient-derived Ewing sarcoma xenograft tumors in mice.
Established…
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- Society AC (2014) American Cancer Society: Cancer Facts and Figures 2014. American Cancer Society, available online.
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- Kaatsch P, Spix C (2014) German Childhood Cancer Registry—Report 2013/14 (1980–2013). Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI) at the University Medical Center of the Johannes Gutenberg University Mainz.
- Animals
- Antineoplastic Agents, Phytogenic / pharmacology*
- Antineoplastic Agents, Phytogenic / therapeutic use
- Apoptosis / drug effects*
- Bone Neoplasms / drug therapy*
- Bone Neoplasms / metabolism
- Bone Neoplasms / pathology
- Caspase 8 / metabolism
- Caspase 9 / metabolism
- Cell Line, Tumor
- Dose-Response Relationship, Drug
- Female
- Heterografts
- Humans
- Mice
- Phytotherapy / methods
- Plant Extracts / pharmacology*
- Plant Extracts / therapeutic use
- Sarcoma, Ewing / drug therapy*
- Sarcoma, Ewing / metabolism
- Sarcoma, Ewing / pathology
- Treatment Outcome
- Viscum album*
- Antineoplastic Agents, Phytogenic
- Plant Extracts
- Caspase 8
- Caspase 9
- Full Text Sources
- Other Literature Sources
- Medical
- Miscellaneous
![Fig 7. ViscumTT reduces the growth of…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5010293/bin/pone.0159749.g007.jpg)
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