The Mechanisms of Mistletoe

The advent of mistletoe therapy for therapeutic applications in cancer care began to take root in the early 1900’s, pioneered by physicians Rudolf Steiner and Ita Wegman. The ideology of mistletoe stems from the principle of the immune system’s response to fever. Therefore, the goal with mistletoe therapy is to enhance warmth which elucidates an immune system response. This involves identification of unhealthy cells, proliferation of appropriate immune mediators, and induction of direct cytotoxic effects. This mechanism is the reason one might expect a pro-inflammatory response upon administration of mistletoe, such as a slight, transient increase in body temperature and/or fatigue. [[i]]

Mistletoe in its natural form exists as a semi-parasitic plant, inhabiting various types of host trees. The tree in which the mistletoe is derived implies some qualities about the mistletoe that may be useful in cancer care. Other variables influencing the qualitative aspects of the mistletoe include time of harvest and extraction method. Mistletoe is most commonly administered via subcutaneous injection or intravenously. This requires careful consideration from an experienced practitioner to determine the type of mistletoe and route of administration that is preferable for a particular circumstance.


Immunologic Effects of Mistletoe

Simply stated, the immune system is divided into two operative systems: innate and adaptive. The innate immune system involves the skin, mucus membranes and several types of non-specific immune cells (natural killer cells, macrophages, neutrophils, mast cells, etc). This is often times the first line of defense and the response occurs very quickly. When mistletoe is applied, an increase in these non-specific cells is increased thereby heightening potential identification and regression of tumor cell activity. [[ii]][[iii]][[iv]][[v]] In fact, a study involving 43 healthy volunteers demonstrated a significant increase in the numbers of the aforementioned cells immediately following mistletoe injection. [[vi]] Particular interest is placed on the effects of mistletoe therapy on indirect stimulation of natural killer cells as these cells have the ability to identify unfavorable cells, especially those within a tumor microenvironment. [[vii]][[viii]] Natural killer cells also elucidate a cytokine or inflammatory response, encouraging the release of various immune mediators. On the other hand, the adaptive immune system typically activates following the innate response and develops as a result of exposure to a specific pathogen (ie: an organism that causes illness or disease such as a bacteria or virus). The intelligence of the immune system lies within the network of the adaptive immune system as this is where memory of pathogen exposure is created which provides long-standing protection. Involvement of cells such as T lymphocytes and B lymphocytes is paramount to this response. Mistletoe has the potential to increase concentration of such immune cells, significantly increasing potential recognition and destruction of tumor cells. [[ix]][[x]][[xi]]


Cytotoxic Effects of Mistletoe

Mistletoe is comprised of various bioactive constituents derived from the whole plant. Two significant elements within mistletoe are lectins and viscotoxins, both of which introduce cytotoxic consequences on malignant cells and modulating actions on the immune system. [[xii]][[xiii]] Mistletoe lectins designate specific carbohydrate groups in which to bind and elicit apoptotic (cell death) effects. [[xiv]] Interestingly, mistletoe is one of the only herbal preparations that is known to contain multiple lectins with varying degrees of apoptotic efficacy. Alternatively, viscotoxins serve as an inherent defense system for the mistletoe plant. However, in the context of cancer, this constituent has an increased affinity for negatively charged cells that are quickly dividing. Once bound, the viscotoxins create pores in the surface of the cell, creating an imbalance and eventually cell lysis. [[xv]]

Overall, the application of mistletoe therapy expands the horizon for synergistic effects against cancer cells and the tumor microenvironment. The addition of this therapy enhances immune function which has strong implications in cancer care.

Resources:

[i] Kienle GS, Kiene H. Review article: Influence of Viscum album L (European mistletoe) extracts on quality of life in cancer patients: a systematic review of controlled clinical studies. Integr Cancer Ther. 2010 Jun;9(2):142-57. doi: 10.1177/1534735410369673. Epub 2010 May 18. PMID: 20483874.

[ii] Gardin NE. Immunological response to mistletoe (Viscum album L.) in cancer patients: a four-case series. Phytother Res. 2009 Mar;23(3):407-11. doi: 10.1002/ptr.2643. PMID: 19003944.

[iii] Baxevanis CN, Voutsas IF, Soler MH, Gritzapis AD, Tsitsilonis OE, Stoeva S, Voelter W, Arsenis P, Papamichail M. Mistletoe lectin I-induced effects on human cytotoxic lymphocytes. I. Synergism with IL-2 in the induction of enhanced LAK cytotoxicity. Immunopharmacol Immunotoxicol. 1998 Aug;20(3):355-72. doi: 10.3109/08923979809034819. PMID: 9736441.

[iv] Kienle GS, Grugel R, Kiene H. Safety of higher dosages of Viscum album L. in animals and humans–systematic review of immune changes and safety parameters. BMC Complement Altern Med. 2011 Aug 28;11:72. doi: 10.1186/1472-6882-11-72. PMID: 21871125; PMCID: PMC3180269.

[v] Tabiasco J, Pont F, Fournié JJ, Vercellone A. Mistletoe viscotoxins increase natural killer cell-mediated cytotoxicity. Eur J Biochem. 2002 May;269(10):2591-600. doi: 10.1046/j.1432-1033.2002.02932.x. PMID: 12027898.

[vi] Huber R, Rostock M, Goedl R, Lüdtke R, Urech K, Buck S, Klein R. Mistletoe treatment induces GM-CSF- and IL-5 production by PBMC and increases blood granulocyte- and eosinophil counts: a placebo controlled randomized study in healthy subjects. Eur J Med Res. 2005 Oct 18;10(10):411-8. PMID: 16287602.

[vii] Tabiasco J, Pont F, Fournié JJ, Vercellone A. Mistletoe viscotoxins increase natural killer cell-mediated cytotoxicity. Eur J Biochem. 2002 May;269(10):2591-600. doi: 10.1046/j.1432-1033.2002.02932.x. PMID: 12027898.

[viii] Büssing A, Rosenberger A, Stumpf C, Schietzel M. Entwicklung lymphozytärer subpopulationen bei tumorpatienten nach subkutaner applikation von mistelextrakten [Development of lymphocyte subsets in tumor patients after subcutaneous administration of mistletoe extracts]. Forsch Komplementarmed. 1999 Aug;6(4):196-204. German. doi: 10.1159/000021253. PMID: 10529579.

[ix] Saha C, Das M, Stephen-Victor E, Friboulet A, Bayry J, Kaveri SV. Differential Effects of Viscum album Preparations on the Maturation and Activation of Human Dendritic Cells and CD4⁺ T Cell Responses. Molecules. 2016 Jul 14;21(7):912. doi: 10.3390/molecules21070912. Erratum in: Molecules. 2019 Oct 18;24(20): PMID: 27428940; PMCID: PMC6273690.

[x] InformedHealth.org [Internet]. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006-. The innate and adaptive immune systems. [Updated 2020 Jul 30]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279396/

[xi] Nikolai G, Friedl P, Werner M, Niggemann B, Zänker KS. Effect of a mistletoe extract (Iscador QuFrF) on viability and migratory behavior of human peripheral CD4+ and CD8+ T lymphocytes in three-dimensional collagen lattices. In Vitro Cell Dev Biol Anim. 1997 Oct;33(9):710-6. doi: 10.1007/s11626-997-0129-8. PMID: 9358287.

[xii] Huber R, Ludtke H, Wieber J, Beckmann C. Safety and effects of two mistletoe preparations on production of Interleukin-6 and other immune parameters- a placebo controlled clinical trial in healthy subjects. BMC Complement Altern Med. 2011;11 (1): 116.

[xiii] Elluru S, Duong van Huyen J, Delignat S, et al. Induction of maturation and activation of human dendritic cells: a mechanism underlying the beneficial effect of Viscum album as complimentary therapy in cancer. BMC Cancer. 2008;8:161.

[xiv] Büssing A, Schietzel M. Apoptosis-inducing properties of Viscum album L. extracts from different host trees, correlate with their content of toxic mistletoe lectins. Anticancer Res. 1999 Jan-Feb;19(1A):23-8. PMID: 10226520.

[xv] Giudici M, Pascual R, de la Canal L, Pfüller K, Pfüller U, Villalaín J. Interaction of viscotoxins A3 and B with membrane model systems: implications to their mechanism of action. Biophys J. 2003 Aug;85(2):971-81. doi: 10.1016/S0006-3495(03)74536-6. PMID: 12885644; PMCID: PMC1303218.

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Dr. Sheila Beades, ND

Dr. Sheila Beades, ND

Dr. Sheila Beades Sheila Beades, N.D. graduated from National University of Health Sciences in Chicago, IL with a degree in Naturopathic Medicine. While there, she completed internships at Whole Health Center and Salvation Army. In years prior to naturopathic school, Dr. Beades obtained her Bachelor’s degree with honors in Biology with a Leadership certificate from Wartburg College in Waverly, IA. In addition, she has pursued further observation and post-graduate training in complementary cancer care and therapies, hormone-related disorders, autoimmune disease, and homeopathy. Dr. Beades is an active member of the Oncology Association of Naturopathic Physicians (OncANP) and the Colorado Association of Naturopathic Physicians (CoAND). Dr. Beades dedicates herself to walking alongside each patient while on their transformational journey back to health. Her passion lies in staying up to date with the latest research, empowering patients through education, and delivering a naturally-focused care plan curated towards the totality of the whole person. In doing so, Dr. Beades supplies the patient with tools to address the underlying disturbances that may be contributing to the current state of health. She believes that the practice of naturopathic medicine should be understandable and doable – which ultimately requires the patient and doctor to collaborate to provide an individualized treatment plan.

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