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Medicinal Applications of Mistletoe Extracts

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Mistletoe-derived substance is extracted from mistletoe plant

Medicinal applications of mistletoe extract involve using mistletoe-derived substances for therapeutic purposes, primarily in cancer treatment and cardiovascular health management.[1][2][3][4][5] In particular, preliminary research demonstrates benefits in reducing cancer therapy side effects and improving treatment outcomes, especially in breast cancer cases.[1][6][7] Animal and cell studies on the cardioprotective effects of mistletoe extract also show promising benefits in treating hypertension and dyslipidemia.[3][4][5]

In cancer therapy, mistletoe extract functions by inducing cancer cell death through lectins and viscotoxins and stimulating the immune system.[8][9] In cardiopathy, lowering blood pressure is primarily investigated to be done through vasodilatory and anti-inflammatory effects, with its proposed mechanism being the nitric oxide pathway.[3][4][5] Mistletoe extract has also been shown to regulate cholesterol levels and treat dyslipidemia through the regulation of HDL and LDL cholesterol.[10]

Mistletoe extract is typically given in the form of a subcutaneous injection,[2] with side effects mild and well tolerated.[11] This includes injection site reactions such as local redness and swelling, flu-like symptoms and diarrhea being most common.[11][12]

Traditional medicines across various cultures have used mistletoe extract to treat a plethora of diseases such as headaches, dermatitis, arthritis, hypertension, asthma, epilepsy, menopausal symptoms, infertility, and rheumatism.[13] In the early 20th century, Rudolf Steiner proposed mistletoe extract as a treatment for cancer, sparking increased interest in its potential therapeutic benefits.[14][15] Today, it is an alternative and complementary therapy for cancer.[1][2] However, further clinical studies are required to confirm its efficacy and safety for conventional use in evidence-based medicine.[14][16][17]

Medical Uses

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Mistletoe extract is considered a complementary alternative medicine (CAM) commonly used in cancer therapies.[1][2] It also demonstrates cardioprotective effects in animal and cell studies.[3][4][5]

Cancer Treatment

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Examples of cytotoxic side effects of chemotherapy

The benefits of using mistletoe extract in cancer therapy mainly focus on how mistletoe extract helps to improve cancer patients’ quality of life.[1][6][7][18] First, the use of mistletoe extract as an add-on therapy can reduce the cytotoxic side effects that cancer patients may experience from chemotherapy.[6][7] Furthermore, mistletoe extract may lengthen the disease-free duration of stage IIb breast cancer patients.[1] Studies also show that mistletoe extract has uplifting effects on the survival of oncologic patients.[14][19] Delving deeper into the scientific aspects, a systematic review concluded that mistletoe extract can induce cancer cell death and stimulate immune system cells.[14]

Although the evidence from some systematic reviews suggests that mistletoe extract brings extra health benefits to cancer patients, most studies included in reviews have several limitations such as small sample size and lack of detailed dosing used in participants.[2] A 2019 systematic review concluded that mistletoe extract has no significant effect on oncologic patients.[20]

Cardiopathy

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The majority of studies on the efficacy of the cardioprotective effects of mistletoe extract come from animal, in-vitro, and in-vivo studies.[3][4][5][10] In general, these studies agree on the ability of mistletoe extract to potentially treat hypertension and heart failure with its vasodilation activity.[3][4][5] Mistletoe extract also shows promising results in its anti-inflammatory activity.[4] Flavonoids, an active ingredient extracted from mistletoe, can moderate the body’s inflammatory activity and act as a potent antioxidant.[4] Some studies have also suggested the ability of mistletoe extract to correct dyslipidemia by lowering serum LDL levels.[4][10]

Although the evidence from some animal studies has suggested the potential cardioprotective effects of mistletoe extract,[3][4][5][10] there is a lack of evidence for the efficacy and safety of mistletoe extract to be used clinically in the human body.

Mechanism Of Action

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Cancer Treatment

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Purified lectins and viscotoxins in mistletoe extracts have shown cytotoxic effects towards cancer cells and immune system mediating activity.[9] This activity is mainly associated with the purified lectin ML-1.[13] The structure of ML-1 contains an alpha chain and beta chain, the former of which is associated with the cytotoxic effect towards cancer cells.[13] The beta chain is speculated to exert binding properties.[13] Though it is suggested that the ML-1 lectin exerts the main pharmacological activity, other studies have reported that a complete mistletoe extract (without excluding any component) is more effective in binding to tumor cells and inducing anti-cancer activity than any given isolated compounds derived from a full extract.[8] Studies show that the amount of lectin-bound cancer cells is positively correlated with survival chance, specifically for patients with breast cancer.[13] However, for adenocarcinoma, a type of cancer that could affect the lung, the amount of mistletoe lectin-bound cells found no benefit in improving survival.[13]

Dendritic cell stimulates CD8+ cells activity, leading to eradication of cancer cells

In terms of indirect benefits of cancer treatment through the strengthening of the immune system, in-vivo studies have suggested that mistletoe extract has immune system stimulating effects, mediating the immune response during cancer treatment.[9][13] Research suggests that mistletoe extract has a role in the maturation of dendritic cells, a type of white blood cell.[8] The activated dendritic cells stimulate further immune response through CD4+ and CD8+ cells, as well as tumour necrosis factor A, all of which contribute immensely towards cancer eradication.[8] The strengthened immune response may also counteract the immunosuppression caused by conventional cancer therapy or increase levels of endorphins in the body,[8][9] both leading to an improved quality of life for patients.

Another pathway was identified for strengthening the immune response, involving an increase in granulocyte and eosinophil counts in the blood.[8] This is mediated by the stimulation of interleukin 5 and granulocyte‐macrophage colony‐stimulating factor, supporting anticancer therapy by enhancing the body's defense against infections.[8]

Cardiopathy

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Molecular pathway of vasodilation mediated by NO & cGMP

Regarding the vasodilatory effects of mistletoe extract, there are two models suggested by different studies. Firstly, the most popular one suggests the regulation of the nitric oxide (NO) pathway.[3][4][5] It is known that NO is crucial in the production of cyclic guanosine monophosphate (cGMP), and consequent downstream interactions with soluble guanylyl cyclase to decrease intracellular calcium ion levels.[3][4][5] This pathway induces cardiac smooth muscle relaxation, vasodilation, and inhibition of platelet aggregation.[4] Mistletoe extract functions by increasing the expression of NOS-2 and NOS-3 (enzymes responsible for increasing circulating NO levels), increasing the biological availability of NO, and hence vasodilation.[4]

However, another model proposed that the vasodilation of mistletoe extract is achieved via the interaction with muscarinic receptors and calcium channels.[21] A study by Radenkovic et al. proposes that mistletoe extract achieves its hypotensive effects through the interaction of flavonoids with muscarinic receptors.[21] Another study suggests the similar theory that mistletoe extract consists of agents capable of binding to beta-2 receptors and hence induces vascular smooth muscle relaxation through parasympathetic activation.[22] Some studies also proposed that mistletoe extract exhibits calcium channel-blocking activity, thus inhibiting smooth muscle contraction and resulting in a drop in blood pressure.[3][4]

In addition to the vasodilatory effects of mistletoe extract, it also shows promising results in the anti-inflammatory activity with the following mechanism of action proposed in studies.[4] Some studies suggested that flavonoids in the extract can moderate inflammatory activity and act as a potent antioxidant.[4] Some other studies proposed another pathway that flavonoids and other phenol structures act as COX-2 inhibitors, and hence mistletoe extract inhibits major inflammatory responses.[4] The inhibition of inflammatory response may be crucial in the indirect lowering of blood pressure and reaching favorable cardiac outcomes.[5]

Mistletoe extract also demonstrates antihyperlipidemic properties with the following mechanism proposed from an animal study.[10] A significant increase in HDL cholesterol and a decrease in LDL cholesterol in rats with dyslipidemia was shown in a study experiment on the effect of Korean mistletoe water.[10] It is proposed that this is mediated through suppressing sterol regulatory element-binding protein-1c (SREBP-1c) and increasing carnitine palmitoyltransferase-1 (CPT-1) expression, resulting in the inhibition of fatty acid genesis in hepatic cells and decreasing triglyceride content.[10] The sterol content of mistletoe extract has also been associated with controlling cardiovascular conditions relating to hypercholesterolemia.[4]

Administration

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Regarding the route of administration, mistletoe extract is normally given as a subcutaneous injection,[2] but sometimes it may be given as off-label intravenous, intratumoral, or intracavitary injections.[8] Examples of commercially available mistletoe injections include Iscador, Isorel, and Helixor.[13]

To prepare the mistletoe injection, either fermented or unfermented extract can be used and they are dissolved in aqueous solutions such as water or alcohol.[13] Different types of injections are commercially available in the market, mainly divided according to the dose given.[9] The phytotherapeutic mistletoe injections are given with a fixed dose of lektines.[4][9] While the anthroposophic and homeopathic mistletoe preparations are given with increased doses based on the patient’s tolerance.[9]

Adverse Effects

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As mistletoe extract is commonly given as an injection, there are potential side effects regarding this route of administration.[11] Common side effects include swelling of the injection site, headache, and fever.[11][12] Other than local discomfort of injection sites, mistletoe extract is relatively safe and side effects vary between the doses used.[16] The most common adverse effect is skin allergic reactions.[1][12] It was estimated that around 12.8% of patients using mistletoe extract experienced mild skin reactions.[1] Apart from minor skin issues, a small number of individuals suffered from anaphylactic shock, a serious allergic response.[11][13]

History

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The therapeutic uses of mistletoe extract among the ancient Greeks and Druids can be traced back centuries.[13] In folklore, mistletoe is regarded as a panacea, able to cure any disease.[13] They include treatment for cancer, epilepsy, infertility, high blood pressure, headaches, and dermatitis.[13] In the ancient tradition of Egypt, mistletoe was used to treat neurological diseases such as epilepsy, and cardiological diseases, such as atherosclerosis, and hypertension.[3]

In 1920, Rudolf Steiner, the founder of anthroposophy, first proposed using mistletoe extract in cancer treatment.[14][15] His proposal was based on the fact that mistletoe is a parasite that kills its host and this process is similar to the killing of cancer cells.[14] Mistletoe extract soon then gained attention as a potential anticancer remedy, with the majority of clinical study findings published in German in the past 100 years.[13] Until now, mistletoe extract has been frequently used in cancer treatment as a complementary alternative medicine (CAM).[1][2]

Regulation

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Up till 2024, mistletoe extract is included in the Homeopathic Pharmacopoeia of the United States but they have not been approved by the U.S. Food and Drug Administration (FDA) to be used as injections in cancer therapy.[2][13] Meanwhile, in Europe, many types of mistletoe extract are frequently prescribed to oncologic patients as CAM.[13] Thus, from a global perspective, the efficacy of mistletoe extract as CAM in cancer treatment remains controversial.[9]

Research Direction

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Cancer Treatment

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With the current limitation regarding the regulatory status of mistletoe extract, chemists and researchers urge more clinical trials with detailed and transparent designs focusing on its safety and efficacy.[14][16][17] They believe that further investigation into mistletoe extract can improve its regulatory status as well as bring valuable insights to future cancer treatments.[14]

Cardiopathy

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Currently, the compounds in mistletoe associated with cardiovascular disease treatment may lack a clear outline of the individual chemical components contributing to its cardioprotective properties.[23] This potentially prevents the knowledge of potential interactions with other cardiovascular medications to be used together or as a possible second or third-line treatment.[23] Additional pharmacokinetic and pharmacodynamic studies are to be conducted to confirm the ideal proportions of the extract and study the different species of mistletoe and their respective host trees.[23] As most studies on mistletoe in cardiology remain as animal and in-vivo and in vitro studies, further clinical trials on humans are needed to determine the therapeutic effects.[23]

References

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  1. ^ a b c d e f g h i Karagöz, A., Kesici, S., Vural, A., Usta, M., Tezcan, B., Semerci, T., & Teker, E. (2016). Cardioprotective effects of Viscum album L. ssp. album (Loranthaceae) on isoproterenol-induced heart failure via regulation of the nitric oxide pathway in rats. The Anatolian Journal of Cardiology. https://doi.org/10.14744/anatoljcardiol.2016.6780
  2. ^ a b c d e f g h Olas, B. (2024). The cardioprotective potential of selected species of mistletoe. Frontiers in Pharmacology, 15. https://doi.org/10.3389/fphar.2024.1395658
  3. ^ a b c d e f g h i j k Szurpnicka, A., Kowalczuk, A., & Szterk, A. (2020). Biological activity of mistletoe: in vitro and in vivo studies and mechanisms of action. Archives of Pharmacal Research, 43(6), 593–629. https://doi.org/10.1007/s12272-020-01247-w
  4. ^ a b c d e f g h i j k l m n o p q r s t Abreu, P., Sánchez, R., Mut, T., Balaguer, D., Latorre, I., & Rodríguez, H. (2016). Homeopathic mistletoe adverse reaction mimics nodal involvement in 18F-FDG PET/CT performed for evaluation of response to chemotherapy in lymphoma. Revista Española De Medicina Nuclear E Imagen Molecular, 36(2), 110–112. https://doi.org/10.1016/j.remn.2016.07.005
  5. ^ a b c d e f g h i j Mistletoe extracts. (2023, June 21). Cancer.gov. https://www.cancer.gov/about-cancer/treatment/cam/patient/mistletoe-pdq
  6. ^ a b c Büssing, A., Raak, C., & Ostermann, T. (2011). Quality of Life and Related Dimensions in Cancer Patients Treated with Mistletoe Extract(Iscador): A Meta-Analysis. Evidence-based Complementary and Alternative Medicine, 2012, 1–8. https://doi.org/10.1155/2012/219402
  7. ^ a b c Complementary cancer therapy: a systematic review of prospective clinical trials on anthroposophic mistletoe extracts. (2007, March 26). PubMed. https://pubmed.ncbi.nlm.nih.gov/17507307/
  8. ^ a b c d e f g h Wider, B., Rostock, M., Huntley, A., Van Ackeren, G., & Horneber, M. (2022). Mistletoe extracts for cancer treatment. Cochrane Library, 2022(8). https://doi.org/10.1002/14651858.cd014782
  9. ^ a b c d e f g h Staupe, H., Buentzel, J., Keinki, C., Buentzel, J., & Huebner, J. (2022). Systematic analysis of mistletoe prescriptions in clinical studies. Journal of Cancer Research and Clinical Oncology, 149(9), 5559–5571. https://doi.org/10.1007/s00432-022-04511-2
  10. ^ a b c d e f g Kim, M. J., Park, J., Kwon, D. Y., Yang, H. J., Kim, D. S., Kang, S., Shin, B. K., Moon, N. R., Song, B., Kim, J., & Park, S. (2014). The supplementation of Korean mistletoe water extracts reduces hot flushes, dyslipidemia, hepatic steatosis, and muscle loss in ovariectomized rats. Experimental Biology and Medicine, 240(4), 477–487. https://doi.org/10.1177/1535370214551693
  11. ^ a b c d e Hutt, N., Kopferschmitt-Kubler, M., Cabalion, J., Purohit, A., Alt, M., & Pauli, G. (2001). Anaphylactic reactions after therapeutic injection of mistletoe (Viscum album L.). Allergologia Et Immunopathologia, 29(5), 201–203. https://doi.org/10.1016/s0301-0546(01)79056-8
  12. ^ a b c Ernst, E., Schmidt, K., & Steuer‐Vogt, M. K. (2003). Mistletoe for cancer? International Journal of Cancer, 107(2), 262–267. https://doi.org/10.1002/ijc.11386
  13. ^ a b c d e f g h i j k l m n o p Mistletoe Extracts (PDQ®). (2024, November 6). Cancer.gov. https://www.cancer.gov/about-cancer/treatment/cam/hp/mistletoe-pdq
  14. ^ a b c d e f g h Ostermann, T., Raak, C., & Büssing, A. (2009). Survival of cancer patients treated with mistletoe extract (Iscador): a systematic literature review. BMC Cancer, 9(1). https://doi.org/10.1186/1471-2407-9-451
  15. ^ a b Ernst, E. (2006). Mistletoe as a treatment for cancer. BMJ, 333(7582), 1282–1283. https://doi.org/10.1136/bmj.39055.493958.80
  16. ^ a b c Kienle, G. S., Glockmann, A., Schink, M., & Kiene, H. (2009). Viscum album L. extracts in breast and gynaecological cancers: a systematic review of clinical and preclinical research. Journal of Experimental & Clinical Cancer Research, 28(1). https://doi.org/10.1186/1756-9966-28-79
  17. ^ a b Horneber, M., Van Ackeren, G., Linde, K., & Rostock, M. (2008). Mistletoe therapy in oncology. Cochrane Library, 2020(11). https://doi.org/10.1002/14651858.cd003297.pub2
  18. ^ Kienle, G. S., & Kiene, H. (2010). Review Article: Influence of Viscum album L (European Mistletoe) Extracts on Quality of Life in Cancer Patients: A Systematic Review of Controlled Clinical Studies. Integrative Cancer Therapies, 9(2), 142–157. https://doi.org/10.1177/1534735410369673
  19. ^ Cazacu, M., Oniu, T., Lungoci, C., Mihailov, A., Cipak, A., Klinger, R., Weiss, T., & Zarkovic, N. (2003). The influence of Isorel on the advanced colorectal cancer. Cancer Biotherapy and Radiopharmaceuticals, 18(1), 27–34. https://doi.org/10.1089/108497803321269304
  20. ^ Freuding, M., Keinki, C., Micke, O., Buentzel, J., & Huebner, J. (2019). Mistletoe in oncological treatment: a systematic review. Journal of Cancer Research and Clinical Oncology, 145(3), 695–707. https://doi.org/10.1007/s00432-018-02837-4
  21. ^ a b Radenkovic, M., Ivetic, V., Popovic, M., Brankovic, S., & Gvozdenovic, L. (2009). Effects of Mistletoe (Viscum AlbumL., Loranthaceae) Extracts on Arterial Blood Pressure in Rats Treated with Atropine Sulfate and Hexocycline. Clinical and Experimental Hypertension, 31(1), 11–19. https://doi.org/10.1080/10641960802409820
  22. ^ Eno, A., & Ofem, O. (2007, May 7). Effect of crude aqueous leaf extract of Viscum album    (mistletoe) in hypertensive rats. https://utoronto.scholaris.ca/items/7597d0a1-d436-4df6-b8ff-25682fa9efae
  23. ^ a b c d Olas, B. (2024b). The cardioprotective potential of selected species of mistletoe. Frontiers in Pharmacology, 15. https://doi.org/10.3389/fphar.2024.1395658
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