43
edits
Changes
Jump to navigation
Jump to search
Line 17:
Line 17: − + + + + + + + + + + + + + + + + + + + + + + + + + Line 41:
Line 65: − + − + − +
→Structure of Mistletoe Lectins: Added several more components of mistletoe
==History of Clinical Use==
==History of Clinical Use==
European Mistletoe (Viscum Album) is the genus with the most scientific interest. It was used historically in traditional European herbal medicine for non-oncologic conditions including epilepsy, hypertension, and heart failure. In 1917 [[Rudolf Steiner]] together with the physician [[Ita Wegman]] developed and used extracts of mistletoe successfully in a case of metastatic breast cancer.<ref>{{Citation | title=van Emmichoven: Wer War Ita Wegman - Google Scholar | url=https://scholar.google.com/scholar_lookup?title=Wer+War+Ita+Wegman&author=ZJ+van+Emmichoven&publication_year=1992& | access-date=13 March 2023}}</ref>
European Mistletoe (Viscum Album) is the genus with the most scientific interest. It was used historically in traditional European herbal medicine for non-oncologic conditions including epilepsy, hypertension, and heart failure. In 1917 [[Rudolf Steiner]] together with the physician [[Ita Wegman]] developed and used extracts of mistletoe successfully in a case of metastatic breast cancer.<ref>{{Citation | title=van Emmichoven: Wer War Ita Wegman - Google Scholar | url=https://scholar.google.com/scholar_lookup?title=Wer+War+Ita+Wegman&author=ZJ+van+Emmichoven&publication_year=1992& | access-date=13 March 2023}}</ref>
==Bioactive Compounds==
===Mistletoe Lectins===
Mistletoe lectins are a member of the type 2 RIP (Ribosomal Inhibitory Compound) family, best known for ricin which has a much less cell specific binding preference and thus potent general toxicity. Lectins are agglutinins, meaning that they have the tendency to cause liquid blood to coagulate into a solid state in their pure form.<ref>{{cite book | vauthors=((Cummings, R. D.)), ((L. Schnaar, R.)) | veditors=((Varki, A.)), ((Cummings, R. D.)), ((Esko, J. D.)), ((Stanley, P.)), ((Hart, G. W.)), ((Aebi, M.)), ((Darvill, A. G.)), ((Kinoshita, T.)), ((Packer, N. H.)), ((Prestegard, J. H.)), ((Schnaar, R. L.)), ((Seeberger, P. H.)) | date= 2015 | chapter=Essentials of Glycobiology | title=R-Type Lectins | publisher=Cold Spring Harbor Laboratory Press | edition=3rd | url=http://www.ncbi.nlm.nih.gov/books/NBK453065/}}</ref> The coalescing tendency of mistletoe lectins is thought of in Anthroposophic-Goetheanistic thinking to relate to the nerve-sense system ([[alchemical Sal process]]) which relates to '''crystal forming activity''', '''sensing and directing,''' and in a plant has its orientation in the '''root'''. Mistletoe lectins are found in high concentrations in the haustorium, its root equivalent, and have specific tumor apoptotic effects and immunomodulating effects on the human organism.<ref>{{cite book | date= 2019 | title=Vademecum of Anthroposophic Medicines. Best Practices for Mistletoe Use in Cancer Care. | publisher=Verlag der Gesellschaft Anthroposophischer Arzte in Deutschland | isbn=978-3-946951-06-3}}</ref> Steiner, long prior to the discovery of mistletoe lectins, gave indications that the mistletoe should be specifically harvested in two harvests, one containing the inner parts of the plant, and the other the outer part, and that these extracts be mixed in a specific way.
[[File:Mistletoe Lectin.jpg|thumb|308x308px|Viscum album agglutinin (VAA-I) consists of two chains. The A-chain (white) with a molecular weight of 29 kDa and with N-glycosidase activity is a potent ribosomal inactivator. The sugar-binding B-chain (green) with a molecular weight of 34 kDa is responsible for the immunomodulatory effect of the molecule. Red colored parts of the B-chain indicate the sugar-binding receptors. (The picture was kindly provided by Madaus Ag, Germany.) Hajtó, T., Hostanska, K., Berki, T., Pálinkás, L., Boldizsár, F., & Németh, P. (2005). Oncopharmacological perspectives of a plant lectin (Viscum album agglutinin-I): overview of recent results from in vitro experiments and in vivo animal models, and their possible relevance for clinical applications. Evidence-Based Complementary and Alternative Medicine, 2(1), 59–67. Published by Oxford University Press.]]
====Structure of Mistletoe Lectins====
Viscum album contains three lectins, differing in their specificity for glycoprotein sites on cell membranes. These are mistletoe lectin 1, 2, and 3 or ML-1, Ml-2, and ML-3. Mistletoe lectin 1 has had the most amount of research. Mistletoe lectins, as members of the type 2 RIP family, are composed of two protein portions linked by a disulfide bond. The A chain is a strong inhibitor of the ribosome, the cellular protein manufacturing organelle. The B chain has strong and selective binding affinity to carbohydrate molecules on the cell surface.<ref>{{cite journal | vauthors=((Hajtó, T.)), ((Hostanska, K.)), ((Berki, T.)), ((Pálinkás, L.)), ((Boldizsár, F.)), ((Németh, P.)) | journal=Evidence-Based Complementary and Alternative Medicine | title=Oncopharmacological perspectives of a plant lectin (Viscum album agglutinin-I): overview of recent results from in vitro experiments and in vivo animal models, and their possible relevance for clinical applications | volume=2 | issue=1 | pages=59–67 | date= 2005}}</ref>
==== Clinical Effects of Mistletoe Lectins ====
In tumor cells mistletoe lectins cause apoptosis by inhibiting the ribosomal subunit. In the human body several immune enhancing effects are noteworthy. Leukocytes and granulocytes are upregulated, and it appears that mistletoe lectins are responsible for the increase in eosinophils seen with mistletoe use.<ref>{{cite journal | vauthors=((R, H.)), ((M, R.)), ((R, G.)), ((R, L.)), ((K, U.)), ((R, K.)) | journal=Journal of the Society for Integrative Oncology | title=Immunologic effects of mistletoe lectins: a placebo-controlled study in healthy subjects | volume=4 | issue=1 | date= Winter 2006 | url=https://pubmed.ncbi.nlm.nih.gov/16737665/ | access-date=2 April 2023}}</ref> Lectins cause the release of the interleukins IL-1 and tumor necrosis factor-α. Dendritic cells, natural killer cells, cytotoxic T cells, and macrophages are upregulated, while T helper cells are modulated in a manner favorable to tumor cell elimination.<ref>{{cite journal | vauthors=((Elluru, S.)), ((Duong Van Huyen, J.-P.)), ((Delignat, S.)), ((Prost, F.)), ((Bayry, J.)), ((Kazatchkine, M. D.)), ((Kaveri, S. V.)) | journal=Arzneimittel-Forschung | title=Molecular mechanisms underlying the immunomodulatory effects of mistletoe (Viscum album L.) extracts Iscador | volume=56 | issue=6A | pages=461–466 | date= June 2006 | doi=10.1055/s-0031-1296813}}</ref>[[File:Viscotoxins.jpg|alt=Molecular model of viscotoxins opening a pore in the tumor cell membrane|left|thumb|The model that describes the action of viscotoxins against tumor cells. "Frequently cited models for activity of antimicrobial peptides. '''a''' AMPs diffusing through solution, '''b''' AMPs adsorption to the membrane. After the threshold concentration is achieved, peptide molecules begin to reorient in the lipid bilayer '''(c)'''. Their further fate may be described using one of three models. The first, depicted in the '''d''' is called barrel-stave model. In this scenario, hydrophobic regions of AMPs align with the tails of the lipids and the hydrophilic residues form the inner surface of the forming pore. According to the wormhole model (called also toroidal pore model, shown in '''e)''' during peptides aggregation, hydrophilic heads of the lipids are electrostatically dragged by charged residues of AMPs. The membrane bends, two layers merge and form continuous surface surrounding the pore. The carpet model shown in '''f''' assumes, that at large concentrations, peptide molecules disrupt the membrane in a detergent-like manner breaking the lipid bilayer into set of separate micelles" from Nawrot, R., Barylski, J., Nowicki, G., Broniarczyk, J., Buchwald, W., & Goździcka-Józefiak, A. (2014). Plant antimicrobial peptides. Folia microbiologica, 59(3), 181–196. <nowiki>https://doi.org/10.1007/s12223-013-0280-4</nowiki>]]
===Viscotoxins===
Viscotoxins are a 46 amino acid long group of compounds with a net positive charge and 3 disulfide bonds. There are 7 isoforms of viscotoxins from viscum album A1, A2, A3, B, B2, 1-PS and C1, with U-PS being an eighth more distantly related compound. Viscotoxins are hypothesized to interact with phosphatidylserine that is a prominent feature of cancer cells membranes, opening a hole in the cell membrane and destabilizing the DNA.<ref>{{cite journal | vauthors=((Samuelsson, G.)), ((Pettersson, B. M.)) | journal=European Journal of Biochemistry | title=The Amino Acid Sequence of Viscotoxin B from the European Mistletoe (Viscum album L, Loranthaceae) | volume=21 | issue=1 | pages=86–89 | date= 1971 | url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1432-1033.1971.tb01443.x | doi=10.1111/j.1432-1033.1971.tb01443.x | access-date=27 March 2023}}</ref><ref>{{cite journal | vauthors=((Pal, A.)), ((Debreczeni, J. É.)), ((Sevvana, M.)), ((Gruene, T.)), ((Kahle, B.)), ((Zeeck, A.)), ((Sheldrick, G. M.)) | journal=Acta Crystallographica Section D Biological Crystallography | title=Structures of viscotoxins A1 and B2 from European mistletoe solved using native data alone | volume=64 | issue=9 | pages=985–992 | date=1 September 2008 | url=https://scripts.iucr.org/cgi-bin/paper?S0907444908022646 | doi=10.1107/S0907444908022646 | access-date=27 March 2023}}</ref><ref>{{cite journal | vauthors=((Nawrot, R.)), ((Barylski, J.)), ((Nowicki, G.)), ((Broniarczyk, J.)), ((Buchwald, W.)), ((Goździcka-Józefiak, A.)) | journal=Folia Microbiologica | title=Plant antimicrobial peptides | volume=59 | issue=3 | pages=181–196 | date= 2014 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971460/ | doi=10.1007/s12223-013-0280-4 | access-date=27 March 2023}}</ref> Viscotoxins have been shown to act as an antimicrobial compound, specifically having anti-fungal activity.<ref>{{cite journal | vauthors=((Giudici, A. M.)), ((Regente, M. C.)), ((Villalaín, J.)), ((Pfüller, K.)), ((Pfüller, U.)), ((De La Canal, L.)) | journal=Physiologia Plantarum | title=Mistletoe viscotoxins induce membrane permeabilization and spore death in phytopathogenic fungi | volume=121 | issue=1 | pages=2–7 | date= 2004 | url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.0031-9317.2004.00259.x | doi=10.1111/j.0031-9317.2004.00259.x | access-date=27 March 2023}}</ref>
=== Oligosaccharides and Polysaccharides ===
Mistletoe extracts contain oligosaccharide compounds that have been found to have an immune stimulating effect on natural killer cells. One oligosaccharide HM-BP has been identified in Helixor Mali and enhances natural killer cells through triggering release of interferon gamma.<ref>{{cite journal | vauthors=((Mueller, E. A.)), ((Anderer, F. A.)) | journal=Cancer immunology, immunotherapy: CII | title=A Viscum album oligosaccharide activating human natural cytotoxicity is an interferon gamma inducer | volume=32 | issue=4 | pages=221–227 | date= 1990 | doi=10.1007/BF01741704}}</ref>
=== Polyphenolic Compounds ===
Depending on the host tree viscum album extracts contain different proportions of phenolic acids. Caffeic, salicylic (primarily from willow host tree), ferulic, and rosmarinic (mostly from apple host tree) acid are found in varying amounts. Mistletoe growing on the ash tree (Abnoba fraxini) has the highest overall amount of polyphenolic compounds.<ref>{{cite journal | vauthors=((Nazaruk, J.)), ((Orlikowski, P.)) | journal=Natural Product Research | title=Phytochemical profile and therapeutic potential of Viscum album L. | volume=30 | issue=4 | pages=373–385 | date=16 February 2016 | url=https://doi.org/10.1080/14786419.2015.1022776 | doi=10.1080/14786419.2015.1022776 | access-date=2 April 2023}}</ref> This quercetin family of compounds exerts apoptotic influences on tumor cells and antioxidant, anti inflammatory, and and pain relieving effects clinically.
=== Terpenoid Compounds ===
Triterpine compounds have been isolated from mistletoe extracts. Betulinic acid is isolated from birch host tree mistletoe and exerts a multitude of anticancer effects, regulating JAK/STAT, VEGF, EGF/EGFR, TRAIL/TRAIL-R, AKT/mTOR and ubiquitination pathways in tumor cells.<ref>{{cite journal | vauthors=((Aa, F.)), ((A, T.)), ((G, T.)), ((A, T.)), ((A, B.)), ((G, K.)), ((S, A.)) | journal=Molecules (Basel, Switzerland) | title=Multifunctional Roles of Betulinic Acid in Cancer Chemoprevention: Spotlight on JAK/STAT, VEGF, EGF/EGFR, TRAIL/TRAIL-R, AKT/mTOR and Non-Coding RNAs in the Inhibition of Carcinogenesis and Metastasis | volume=28 | issue=1 | date=21 December 2022 | url=https://pubmed.ncbi.nlm.nih.gov/36615262/ | doi=10.3390/molecules28010067 | access-date=2 April 2023}}</ref> Other triterpenes isolated from mistletoe extracts are b-amyrin acetate and oleanolic acid. As these are poorly water soluable the manufacturers use extraction techniques to enhance these compounds in their extracts.
==Scientific Evidence==
==Scientific Evidence==
===Meta-analysis===
===Meta-analysis===
====Büssing et al 2012====
====[[Quality of Life and Related Dimensions in Cancer Patients Treated with Mistletoe Extract (Iscador): A Meta-Analysis|Büssing et al 2012]]====
<gallery widths="500" heights="500" perrow="2">
<gallery widths="500" heights="500" perrow="2">
File:Bussing et al 2012 meta analysis.jpg|Meta analysis standard mean difference effects showing an overall treatment effect at SMD = 0.56 (CI: 0.41 to 0.71, ''P'' < .0001), indicating a moderate effect.
File:Bussing et al 2012 meta analysis.jpg|Meta analysis standard mean difference effects showing an overall treatment effect at SMD = 0.56 (CI: 0.41 to 0.71, ''P'' < .0001), indicating a moderate effect.
File:Bussing plausible cause of QOL.jpg|Hypothetical diagram explaining the possible mechanisms of ''Viscum album'' extract application on QoL. Büssing, A., Raak, C., & Ostermann, T. (2012). Quality of Life and Related Dimensions in Cancer Patients Treated with Mistletoe Extract (Iscador): A Meta-Analysis. ''Evidence-Based Complementary and Alternative Medicine : ECAM'', ''2012'', 219402. https://doi.org/10.1155/2012/21940
File:Bussing plausible cause of QOL.jpg|Hypothetical diagram explaining the possible mechanisms of ''Viscum album'' extract application on QoL. Büssing, A., Raak, C., & Ostermann, T. (2012). Quality of Life and Related Dimensions in Cancer Patients Treated with Mistletoe Extract (Iscador): A Meta-Analysis. ''Evidence-Based Complementary and Alternative Medicine : ECAM'', ''2012'', 219402. https://doi.org/10.1155/2012/21940
</gallery>Büssing et al examined 734 patients treated with subcutaneous Iscador versus 741 controls in 13 controlled trials (9 of which were randomized) and looked at differences in quality of life.<ref>{{cite journal | vauthors=((Büssing, A.)), ((Raak, C.)), ((Ostermann, T.)) | journal=Evidence-based Complementary and Alternative Medicine : eCAM | title=Quality of Life and Related Dimensions in Cancer Patients Treated with Mistletoe Extract (Iscador): A Meta-Analysis | volume=2012 | pages=219402 | date= 2012 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124023/ | doi=10.1155/2012/219402 | access-date=16 March 2023}}</ref> Though the included studies suffered from
</gallery>[[Quality of Life and Related Dimensions in Cancer Patients Treated with Mistletoe Extract (Iscador): A Meta-Analysis|Büssing et al]] examined 734 patients treated with subcutaneous Iscador versus 741 controls in 13 controlled trials (9 of which were randomized) and looked at differences in quality of life.<ref>{{cite journal | vauthors=((Büssing, A.)), ((Raak, C.)), ((Ostermann, T.)) | journal=Evidence-based Complementary and Alternative Medicine : eCAM | title=Quality of Life and Related Dimensions in Cancer Patients Treated with Mistletoe Extract (Iscador): A Meta-Analysis | volume=2012 | pages=219402 | date= 2012 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124023/ | doi=10.1155/2012/219402 | access-date=16 March 2023}}</ref> Though the included studies suffered from
quality issues such as lacking description of intention to treat analysis, compliance, and enrolled less than 200 patients, most trials were randomized and all of the results pointed to significant quality of life effects, despite high heterogeneity.
quality issues such as lacking description of intention to treat analysis, compliance, and enrolled less than 200 patients, most trials were randomized and all of the results pointed to significant quality of life effects, despite high heterogeneity.
====Ernst et al 2003====
====Ernst et al 2003====
Ernst et al examined 10 randomized controlled trials. They did not perform statistical analysis because of heterogeneity and concluded an overall lack of benefit of mistletoe. Though they did comment on quality issues with the respective trials, 6 of the 10 actually did report a benefit.<ref>{{cite journal | vauthors=((Ernst, E.)), ((Schmidt, K.)), ((Steuer-Vogt, M. K.)) | journal=International Journal of Cancer | title=Mistletoe for cancer? A systematic review of randomised clinical trials | volume=107 | issue=2 | pages=262–267 | date=1 November 2003 | doi=10.1002/ijc.11386}}</ref> [[Edzard Ernst]] is a well known integrative medicine skeptic, publishing dozens of review articles on integrative modalities from acupuncture to chiropractic all with negative findings.<ref>{{Citation | title=Edzard Ernst | Skeptical About Skeptics | url=https://skepticalaboutskeptics.org/investigating-skeptics/whos-who-of-media-skeptics/edzard-ernst/ | access-date=17 March 2023}}</ref>
Ernst et al examined 10 randomized controlled trials. They did not perform statistical analysis because of heterogeneity and concluded an overall lack of benefit of mistletoe. Though they did comment on quality issues with the respective trials, 6 of the 10 actually did report a benefit.<ref>{{cite journal | vauthors=((Ernst, E.)), ((Schmidt, K.)), ((Steuer-Vogt, M. K.)) | journal=International Journal of Cancer | title=Mistletoe for cancer? A systematic review of randomised clinical trials | volume=107 | issue=2 | pages=262–267 | date=1 November 2003 | doi=10.1002/ijc.11386}}</ref> [[Wikipedia:Edzard Ernst|Edzard Ernst]] is a well known integrative medicine [[skeptic]], publishing dozens of review articles on integrative modalities from [[acupuncture]] to [[chiropractic]] all with negative findings.<ref>{{Citation | title=Edzard Ernst | Skeptical About Skeptics | url=https://skepticalaboutskeptics.org/investigating-skeptics/whos-who-of-media-skeptics/edzard-ernst/ | access-date=17 March 2023}}</ref>
====Cochrane Review====
====Cochrane Review====