- Email: [email protected]
Whole mistletoe extract viscumTT has anti-cancer effects in osteosarcoma in vitro and in vivo
Phytomedicine 22 (2015) S11–S14
Contents lists available at ScienceDirect
Phytomedicine journal homepage: www.elsevier.com/locate/phymed
Mistletoe in Tumour Therapy. Basic Research and Clinical Practice. 6th Mistletoe Symposium
Medicinal use of mistletoes in Mato Grosso, Brazil Arno Rieder a,∗, Orivaldo Benedito da Silva b, Luciene da Costa Rodrigues b, Fabiana Aparecida Caldart Rodrigues b, Dardi Antonia Soares da Silva c a Multi-Inter-Dept
(Mathematics, Biology, Agronomy and Nursing), Campus of Cáceres (CUC), University of Mato Grosso State (UNEMAT), Cáceres, Mato Grosso (MT), Brazil (BR) b Dept of Biology, CUC, UNEMAT, Cáceres, MT, BR c Dept of Medicine, CUC, UNEMAT, Cáceres, MT, BR ∗
Corresponding author. Tel.: +55 065 99983493. E-mail address: [email protected]
Purpose: Several species of mistletoe are used to treat cancer. We here present a study on popular medicinal uses of various mistletoe species occurring in Brazilian urban environment. Methods: The study was conducted in Cáceres, Mato Grosso, Brazil, and nearby in February 2015. Local healers verified the various medicinal uses. Results: We identified three species of Loranthaceae [Passovia pedunculata (Jacq.) Kuijt, Psittacanthus acinarius (Mart.) Mart., Psittacanthus cordatus (Hoffmanns.) G. Don] and two Santalaceae [Phoradendron piperoides (Kunth) Trel., Phoradendron sp.]. P. pedunculata and P. acinarius are reported by healers to be used to treat cancer. P. acinarius is also reported to be used to treat wounds, ulcers, various infections, systems disorders (skin, urinary, respiratory, cardiovascular and reproductive) and diabetes. The literature confirms the use of members of the genus Psittacanthus as aseptic and hypotensive. Several mistletoe species are used by various tribes of America as medication, food and tea, in South Africa they are applied to relieve pain and low back pain; in Japan against hypertension and rheumatism. Some mistletoe species showed antioxidant activity and also analgesic, anti-inflammatory, immune-stimulating, anti-hyperglycaemic, neuroprotective, and anti-hypertensive activities. Laboratory tests using Phthirusa adunca and P. pyrifolia preparations revealed several effects, such as vasodilatory, antihypertensive, bactericidal and fungicidal. Cytotoxic, antitumour, anticancer and immunomodulatory activities of mistletoes are assigned to lectins. Lectins and polysaccharides of mistletoes are promising in alternative therapies in cancer. Mistletoes extracts strengthen immunity, delay the onset and tumour progression and/or eliminate it. They are known to relieve side effects of chemotherapy. The fisetin, which is contained in mistletoes, inhibits the proliferation of cancer cells and induce apoptosis. http://dx.doi.org/10.1016/j.phymed.2015.05.019 0944-7113
Conclusions: In this region mistletoes are used to treat cancer and other diseases. There are few publications addressing bioactivity, efficacy and safety. These issues have to be addressed in future. Keywords: anti-cancer plants, Passovia, Phoradendron, Phthirusa, Psittacanthus Acknowledgements: We thank Dr. Claudenir Simões Caires for help in species identification and UNEMAT, CNPq and FLOBIO Group (Study of Plant Bioactive) for support and scholarships. doi: 10.1016/j.phymed.2015.05.020 Whole mistletoe extract viscumTT has anti-cancer effects in osteosarcoma in vitro and in vivo Susann Kleinsimon a, Catharina I. Delebinski a, Gwenda Kauczor a, Sebastian Jäger b, Jana Rolff c, Angelika Eggert a, Georg Seifert a,∗ a Department
of Pediatric Oncology/ Hematology, Otto-Heubner-Centre for Pediatric and Adolescent Medicine (OHC), Charité, Universitätsmedizin Berlin, Germany b Birken AG Niefern-Öschelbronn, Germany c EPO Berlin-Buch GmbH, Germany ∗
Corresponding author. Tel.: + 49 30 450 666 087; fax: +49 30 450 566 906. E-mail address: [email protected] Purpose: Paediatric osteosarcoma is the most common malignant solid bone tumour. It is highly metastatic and associated with a poor prognosis. Aqueous mistletoe extracts (Viscum album L.) are widely applied in complementary cancer therapy. Besides watersoluble lectins and viscotoxins the plant extract contains waterinsoluble triterpene acids which are known for their anti-cancer potential. Using cyclodextrins it was possible to solubilise mistletoe triterpenes, mainly oleanolic acid. Single agents of mistletoe triterpenes and lectins and the combination thereof were analysed with regard to its anti-cancer effects on osteosarcoma. Methods: Different osteosarcoma cell lines (143B-HOS, SaOS-2) were treated with mistletoe lectins and viscotoxins (viscum) or solubilised oleanolic- and betulinic acids (TT) and more interestingly with the combination (viscumTT). Apoptosis was confirmed by CASP8 and CASP9 activity assay, inhibitor assay and cell cycle analysis via flow cytometry. In addition, proteins of BCL-2 and inhibitor of apoptosis proteins (IAPs) families were analysed by western blots.
S12
Abstracts / Phytomedicine 22 (2015) S11–S14
Results: TT and viscumTT induced apoptosis by activation of CASP8 and CASP9 and mitochondria impairment in SaOS-2 and 143B-HOS cells. On the contrary, both cell lines were less sensitive to viscum. Furthermore, viscumTT was able to induce apoptosis in a synergistic manner. TT and viscumTT decreased the level of BCL-2. XIAP and BIRC5 were down-regulated by viscum, TT and viscumTT. TT alone induced G0/1 arrest. Furthermore, a significantly reduced tumour growth was observed after VAE treatment in vivo. Conclusion: We could show that viscumTT possesses the strongest anti-cancer effects in vitro, in vivo and ex vivo. Moreover the mouse model confirmed the therapeutic effectiveness of viscumTT treatment resulting in significant tumour volume reduction. Hence, more attention to mistletoe treatment as adjuvant therapy beside conventional therapy is advisable. Keywords: mistletoe, osteosarcoma, apoptosis, oleanolic acid, Viscum album L
ous exposition of cancer cells to VAE and chemotherapeutic drugs, as well as the anti-estrogen tamoxifen and the monoclonal antibody herceptin. Keywords: complementary and alternative medicine (CAM), herb drug interactions, mistletoe (Viscum album), chemotherapy, breast cancer treatment
doi: 10.1016/j.phymed.2015.05.021
∗
Interaction of mistletoe preparations (Viscum album) with antitumour effects of several standard anticancer drugs in vitro
Purpose: The main immuno-stimulating component of mistletoe extract, mistletoe lectin, recently has been shown to be a pattern recognition receptor ligand (PRRL), hence is binding to an important class of pathogen sensing receptors. Pattern recognition receptor ligands are potent activators of dendritic cells (DC). DC activation is a prerequisite for a full-blown T-cell response against cancer cells. We tested single and combined PRRL in vivo in a mouse cancer model. Methods: We collect evidence from experiments in a mouse cancer model and from protein structure comparisons to argue that a combination of mistletoe therapy with other pattern recognition receptor ligand-substances leads to an increased immune stimulatory effect. Results: We show that mistletoe lectin is a plant protein of bacterial origin with a 3D structure very similar to shiga toxin from Shigella dysenteriae, which explains the remarkable immunogenicity of mistletoe lectin. Secondly, we show that a combination of pattern recognition receptor ligands applied metronomically in a cancer mouse model leads to complete remission, while single pattern recognition receptor ligands slowed tumour growth. Conclusions: Taken together, we propose to combine mistletoe drugs with other pattern recognition receptor ligand-drugs to increase its efficacy in adjuvant or even primary cancer therapy. Keywords: mistletoe lectin; pattern recognition receptor ligand; shiga toxin; cancer immunotherapy
a Hiscia
Institute, Iscador AG, Arlesheim, Switzerland of Integrative Medicine, Witten/Herdecke Herdecke, Germany
Mistletoe lectin in concert Claudia Maletzki a, Michael Linnebacher a, Rajkumar Savai b, Uwe Hobohm c,∗ a University
of Rostock, Rostock, Germany Planck Institute for Heart and Lung Research, Bad Nauheim, Germany c University of Applied Sciences, Giessen, Germany b Max
Corresponding author. Tel.: +49 641 3092347. E-mail address: [email protected]
Ulrike Weissenstein a,∗, Matthias Kunz a, Konrad Urech a, Stephan Baumgartner a,b b Institute
doi: 10.1016/j.phymed.2015.05.022
University,
∗
Corresponding author. Tel.: +41 61 706 72 55; fax: +41 61 706 72 64. E-mail address: [email protected] Purpose: Given the importance of complementary and alternative medicine (CAM) to cancer patients, there is an increasing need to learn more about interactions between CAM and anticancer drugs. Mistletoe (Viscum album L.) belongs to the medicinal herbs that are used as supportive care during standard anticancer therapy. To upgrade the knowledge of possible herb-drug interactions between CAM and conventional anticancer medications, we investigated possible effects of mistletoe preparations on the in vitro efficacy of several common conventional chemotherapeutic drugs as well as on two widely used drugs for the treatment of breast cancer. Methods: Several human carcinoma cell lines were treated with the cytostatic drugs doxorubicin hydrochloride, gemcitabine hydrochloride, docetaxel, mitoxantrone hydrochloride or cisplatin, respectively. An estrogen receptor positive human breast carcinoma cell line was treated with (E/Z)-endoxifen hydrochloride, a tamoxifen metabolite in the presence and absence of defined estrogen concentrations. A Her-2 positive human breast carcinoma cell line was treated with the humanized recombinant monoclonal antibody trastuzumab (herceptin). Each dose of the respective drug was combined with Viscum album extract (VAE: Iscador Q spez. or Iscador M spez.) in clinically relevant concentrations. Proliferation, apoptosis and in some cases cell cycle and vascular endothelial growth factor (VEGF)-expression were measured. Results: VAE did not inhibit chemotherapy induced cytostasis and cytotoxicity in any of our experimental settings. At higher concentrations VAE showed an additive inhibitory effect. Moreover the mechanisms of action of trastuzumab and tamoxifen which differ clearly from chemotherapeutic drugs was not impaired by the influence of VAE either. Conclusions: Our in vitro results suggest that no risk of safety by herb drug interactions has to be expected from the simultane-
Reference Maletzki, C., Linnebacher, M., Savai, R., Hobohm, U., 2013. Mistletoe lectin has a shiga toxin-like structure and should be combined with other toll-like receptor ligands in cancer therapy. Cancer Immunol Immunother 62, 1283–1292.
doi: 10.1016/j.phymed.2015.05.068 Viscum album and its anti-inflammatory effect: angle of cytokine induced selective inhibition of COX-2 Chaitrali Saha a,b,c, Alain Friboulet b, Jagadeesh Bayry a,c,d,e, Srinivas V Kaveri a,c,d,e,∗ a Institut
National de la Santé et de la Recherche Médicale, Unité 1138, Paris, France b Université de Technologie de Compiègne, UMR CNRS 6022, Compiègne, France
Contents lists available at ScienceDirect
Phytomedicine journal homepage: www.elsevier.com/locate/phymed
Mistletoe in Tumour Therapy. Basic Research and Clinical Practice. 6th Mistletoe Symposium
Medicinal use of mistletoes in Mato Grosso, Brazil Arno Rieder a,∗, Orivaldo Benedito da Silva b, Luciene da Costa Rodrigues b, Fabiana Aparecida Caldart Rodrigues b, Dardi Antonia Soares da Silva c a Multi-Inter-Dept
(Mathematics, Biology, Agronomy and Nursing), Campus of Cáceres (CUC), University of Mato Grosso State (UNEMAT), Cáceres, Mato Grosso (MT), Brazil (BR) b Dept of Biology, CUC, UNEMAT, Cáceres, MT, BR c Dept of Medicine, CUC, UNEMAT, Cáceres, MT, BR ∗
Corresponding author. Tel.: +55 065 99983493. E-mail address: [email protected]
Purpose: Several species of mistletoe are used to treat cancer. We here present a study on popular medicinal uses of various mistletoe species occurring in Brazilian urban environment. Methods: The study was conducted in Cáceres, Mato Grosso, Brazil, and nearby in February 2015. Local healers verified the various medicinal uses. Results: We identified three species of Loranthaceae [Passovia pedunculata (Jacq.) Kuijt, Psittacanthus acinarius (Mart.) Mart., Psittacanthus cordatus (Hoffmanns.) G. Don] and two Santalaceae [Phoradendron piperoides (Kunth) Trel., Phoradendron sp.]. P. pedunculata and P. acinarius are reported by healers to be used to treat cancer. P. acinarius is also reported to be used to treat wounds, ulcers, various infections, systems disorders (skin, urinary, respiratory, cardiovascular and reproductive) and diabetes. The literature confirms the use of members of the genus Psittacanthus as aseptic and hypotensive. Several mistletoe species are used by various tribes of America as medication, food and tea, in South Africa they are applied to relieve pain and low back pain; in Japan against hypertension and rheumatism. Some mistletoe species showed antioxidant activity and also analgesic, anti-inflammatory, immune-stimulating, anti-hyperglycaemic, neuroprotective, and anti-hypertensive activities. Laboratory tests using Phthirusa adunca and P. pyrifolia preparations revealed several effects, such as vasodilatory, antihypertensive, bactericidal and fungicidal. Cytotoxic, antitumour, anticancer and immunomodulatory activities of mistletoes are assigned to lectins. Lectins and polysaccharides of mistletoes are promising in alternative therapies in cancer. Mistletoes extracts strengthen immunity, delay the onset and tumour progression and/or eliminate it. They are known to relieve side effects of chemotherapy. The fisetin, which is contained in mistletoes, inhibits the proliferation of cancer cells and induce apoptosis. http://dx.doi.org/10.1016/j.phymed.2015.05.019 0944-7113
Conclusions: In this region mistletoes are used to treat cancer and other diseases. There are few publications addressing bioactivity, efficacy and safety. These issues have to be addressed in future. Keywords: anti-cancer plants, Passovia, Phoradendron, Phthirusa, Psittacanthus Acknowledgements: We thank Dr. Claudenir Simões Caires for help in species identification and UNEMAT, CNPq and FLOBIO Group (Study of Plant Bioactive) for support and scholarships. doi: 10.1016/j.phymed.2015.05.020 Whole mistletoe extract viscumTT has anti-cancer effects in osteosarcoma in vitro and in vivo Susann Kleinsimon a, Catharina I. Delebinski a, Gwenda Kauczor a, Sebastian Jäger b, Jana Rolff c, Angelika Eggert a, Georg Seifert a,∗ a Department
of Pediatric Oncology/ Hematology, Otto-Heubner-Centre for Pediatric and Adolescent Medicine (OHC), Charité, Universitätsmedizin Berlin, Germany b Birken AG Niefern-Öschelbronn, Germany c EPO Berlin-Buch GmbH, Germany ∗
Corresponding author. Tel.: + 49 30 450 666 087; fax: +49 30 450 566 906. E-mail address: [email protected] Purpose: Paediatric osteosarcoma is the most common malignant solid bone tumour. It is highly metastatic and associated with a poor prognosis. Aqueous mistletoe extracts (Viscum album L.) are widely applied in complementary cancer therapy. Besides watersoluble lectins and viscotoxins the plant extract contains waterinsoluble triterpene acids which are known for their anti-cancer potential. Using cyclodextrins it was possible to solubilise mistletoe triterpenes, mainly oleanolic acid. Single agents of mistletoe triterpenes and lectins and the combination thereof were analysed with regard to its anti-cancer effects on osteosarcoma. Methods: Different osteosarcoma cell lines (143B-HOS, SaOS-2) were treated with mistletoe lectins and viscotoxins (viscum) or solubilised oleanolic- and betulinic acids (TT) and more interestingly with the combination (viscumTT). Apoptosis was confirmed by CASP8 and CASP9 activity assay, inhibitor assay and cell cycle analysis via flow cytometry. In addition, proteins of BCL-2 and inhibitor of apoptosis proteins (IAPs) families were analysed by western blots.
S12
Abstracts / Phytomedicine 22 (2015) S11–S14
Results: TT and viscumTT induced apoptosis by activation of CASP8 and CASP9 and mitochondria impairment in SaOS-2 and 143B-HOS cells. On the contrary, both cell lines were less sensitive to viscum. Furthermore, viscumTT was able to induce apoptosis in a synergistic manner. TT and viscumTT decreased the level of BCL-2. XIAP and BIRC5 were down-regulated by viscum, TT and viscumTT. TT alone induced G0/1 arrest. Furthermore, a significantly reduced tumour growth was observed after VAE treatment in vivo. Conclusion: We could show that viscumTT possesses the strongest anti-cancer effects in vitro, in vivo and ex vivo. Moreover the mouse model confirmed the therapeutic effectiveness of viscumTT treatment resulting in significant tumour volume reduction. Hence, more attention to mistletoe treatment as adjuvant therapy beside conventional therapy is advisable. Keywords: mistletoe, osteosarcoma, apoptosis, oleanolic acid, Viscum album L
ous exposition of cancer cells to VAE and chemotherapeutic drugs, as well as the anti-estrogen tamoxifen and the monoclonal antibody herceptin. Keywords: complementary and alternative medicine (CAM), herb drug interactions, mistletoe (Viscum album), chemotherapy, breast cancer treatment
doi: 10.1016/j.phymed.2015.05.021
∗
Interaction of mistletoe preparations (Viscum album) with antitumour effects of several standard anticancer drugs in vitro
Purpose: The main immuno-stimulating component of mistletoe extract, mistletoe lectin, recently has been shown to be a pattern recognition receptor ligand (PRRL), hence is binding to an important class of pathogen sensing receptors. Pattern recognition receptor ligands are potent activators of dendritic cells (DC). DC activation is a prerequisite for a full-blown T-cell response against cancer cells. We tested single and combined PRRL in vivo in a mouse cancer model. Methods: We collect evidence from experiments in a mouse cancer model and from protein structure comparisons to argue that a combination of mistletoe therapy with other pattern recognition receptor ligand-substances leads to an increased immune stimulatory effect. Results: We show that mistletoe lectin is a plant protein of bacterial origin with a 3D structure very similar to shiga toxin from Shigella dysenteriae, which explains the remarkable immunogenicity of mistletoe lectin. Secondly, we show that a combination of pattern recognition receptor ligands applied metronomically in a cancer mouse model leads to complete remission, while single pattern recognition receptor ligands slowed tumour growth. Conclusions: Taken together, we propose to combine mistletoe drugs with other pattern recognition receptor ligand-drugs to increase its efficacy in adjuvant or even primary cancer therapy. Keywords: mistletoe lectin; pattern recognition receptor ligand; shiga toxin; cancer immunotherapy
a Hiscia
Institute, Iscador AG, Arlesheim, Switzerland of Integrative Medicine, Witten/Herdecke Herdecke, Germany
Mistletoe lectin in concert Claudia Maletzki a, Michael Linnebacher a, Rajkumar Savai b, Uwe Hobohm c,∗ a University
of Rostock, Rostock, Germany Planck Institute for Heart and Lung Research, Bad Nauheim, Germany c University of Applied Sciences, Giessen, Germany b Max
Corresponding author. Tel.: +49 641 3092347. E-mail address: [email protected]
Ulrike Weissenstein a,∗, Matthias Kunz a, Konrad Urech a, Stephan Baumgartner a,b b Institute
doi: 10.1016/j.phymed.2015.05.022
University,
∗
Corresponding author. Tel.: +41 61 706 72 55; fax: +41 61 706 72 64. E-mail address: [email protected] Purpose: Given the importance of complementary and alternative medicine (CAM) to cancer patients, there is an increasing need to learn more about interactions between CAM and anticancer drugs. Mistletoe (Viscum album L.) belongs to the medicinal herbs that are used as supportive care during standard anticancer therapy. To upgrade the knowledge of possible herb-drug interactions between CAM and conventional anticancer medications, we investigated possible effects of mistletoe preparations on the in vitro efficacy of several common conventional chemotherapeutic drugs as well as on two widely used drugs for the treatment of breast cancer. Methods: Several human carcinoma cell lines were treated with the cytostatic drugs doxorubicin hydrochloride, gemcitabine hydrochloride, docetaxel, mitoxantrone hydrochloride or cisplatin, respectively. An estrogen receptor positive human breast carcinoma cell line was treated with (E/Z)-endoxifen hydrochloride, a tamoxifen metabolite in the presence and absence of defined estrogen concentrations. A Her-2 positive human breast carcinoma cell line was treated with the humanized recombinant monoclonal antibody trastuzumab (herceptin). Each dose of the respective drug was combined with Viscum album extract (VAE: Iscador Q spez. or Iscador M spez.) in clinically relevant concentrations. Proliferation, apoptosis and in some cases cell cycle and vascular endothelial growth factor (VEGF)-expression were measured. Results: VAE did not inhibit chemotherapy induced cytostasis and cytotoxicity in any of our experimental settings. At higher concentrations VAE showed an additive inhibitory effect. Moreover the mechanisms of action of trastuzumab and tamoxifen which differ clearly from chemotherapeutic drugs was not impaired by the influence of VAE either. Conclusions: Our in vitro results suggest that no risk of safety by herb drug interactions has to be expected from the simultane-
Reference Maletzki, C., Linnebacher, M., Savai, R., Hobohm, U., 2013. Mistletoe lectin has a shiga toxin-like structure and should be combined with other toll-like receptor ligands in cancer therapy. Cancer Immunol Immunother 62, 1283–1292.
doi: 10.1016/j.phymed.2015.05.068 Viscum album and its anti-inflammatory effect: angle of cytokine induced selective inhibition of COX-2 Chaitrali Saha a,b,c, Alain Friboulet b, Jagadeesh Bayry a,c,d,e, Srinivas V Kaveri a,c,d,e,∗ a Institut
National de la Santé et de la Recherche Médicale, Unité 1138, Paris, France b Université de Technologie de Compiègne, UMR CNRS 6022, Compiègne, France