Mistletoe Magic: Harnessing Nature’s Remedies in Cancer Therapy
By Eva Fata
Mistletoe is a semiparasitic plant which grows on many types of trees such as oak, maple, elm, pine and poplar. It has been used for hundreds of years to treat medical conditions like epilepsy, asthma, hypertension, headaches, arthritis and many more.
However, what most people don’t know is that mistletoe therapy can used as complementary and/or alternative therapies for cancer. In fact, in Europe, mistletoe extracts are the most prescribed therapies for cancer patients! I will be talking about the hidden wonders of mistletoe therapy and how it kills cancer.
Mistletoe extracts are made in water-based solutions or solutions of water and alcohol. Mistletoe products can be named by the type of tree which the plant grows. For example, IscadorP comes from pine trees, IscadorQu comes from oak trees and IscadorU comes from elm trees.
Mistletoe extracts are usually given by injection under the skin. Other less common ways include by mouth, into a vein, into the pleural cavity or a tumour. Most people take subcutaneous injections, which are given 2 to 3 times a week, however, this can vary.
How does mistletoe work?
The mistletoe extracts have been shown to kill cancer cells in vitro to down-regulate central genes involved in tumour progression, malignancy, cell migration and invasions like TGF beta and matrix-metalloproteinases.
Mistletoe extracts have been shown to:
- enforce natural killer cell-mediated tumour cell lysis
- reduce the migratory and invasive potential of tumour cells
- stimulate immune system cells both in vitro and in vivo
Three components of mistletoe, viscotoxins and lectins are responsible for these effects. Viscotoxins are small proteins which exhibit cell-killing activity and possible immune system-stimulating activity. Lectins are complex molecules which are made of both protein and carbohydrates and are capable of binding to the outside of cells (immune system cells) and prompting biochemical changes in them.
Mistletoe’s ability to stimulate the immune system has been classified as a type of biological response modifier. Biological response modifiers are a diverse group of biological molecules which have been used individually or in combination with other agents to treat cancer or lessen the side effects which come along with anticancer drugs. In addition, mistletoe extract has been shown to have other mechanisms of action like antiangiogenesis.
Preparations of Mistletoe
Preparations from mistletoe extracts are frequently used for cancer patients in German-speaking countries. Some commercially available extracts are marketed under a variety of brand names like Iscafor, Eurixor, Helixor, Isorel, Iscucin, Plenosol and abnobaVISCUM. All of these products are prepared from the Viscum album (Loranthaceae) (Viscum album L. or European mistletoe). They are not sold as a drug in the United States. Eurixor, Isorel, and Vysorel are no longer commercially available. In addition to European mistletoe, extracts from Korean mistletoe (Viscum album var. coloratum [Kom.] Ohwi) have been shown in virto and in vivo cytotoxicity in lab studies.
Mistletoe extract grows on several different types of trees, and therefore the chemical composition of the extract depends on:
- Species of the tree (oak, pine, spruce apple etc)
- Time of the year in which it was harvested
- How the extracts are prepared
- The commercial producer
Mistletoe extracts are prepared as aqueous solutions or solutions of water and alcohol and can be fermented or unfermented. Some extracts are prepared according to homeopathic preparations and others aren’t. Homeopathic preparations are typically not chemically standardized extracts.
Commercial products are subdivided according to the species of the tree which is usually indicated in the product name by a suffix letter. For example Iscador, a fermented aqueous extract of Viscum album L. prepared as a homeopathic drug is marketed as one of the following:
- IscadorM (from apple trees; Malus domestica).
- IscadorP (from pine trees; Pinus sylvestris).
- IscadorQu (from oak trees; Quercus robur).
- IscadorU (from elm trees; Ulmus minor).
Helixor which is an unfermented aqueous extract of Viscum album L. which is known by its biological effect on human leukemia cells in vitro is marked as:
- HelixorA (from spruce trees).
- HelixorM (from apple trees).
- HelixorP (from pine trees).
Eurixor is an unfermented aqueous extract of Viscum album L. harvested from poplar trees, contains a specific amount of one of the mistletoe’s lectins ( lectin ML-1)
Lectins Involved in Mistletoe Therapy
Galectins
Galectins are a family of proteins which have a high affinity for binding to sugar molecules that contain β-galactoside residues. They are found in many animals and have been involved in multiple biological processes, including cancer progression.
Intracellular Galectin-3
In the intracellular environment, galectin-3 has been associated with several pro-cancerous effects. For example, it interacts with a thyroid-specific transcription factor called TTF-1. This leads to a promotion of thyroid cell proliferation which can in turn contribute to the development of tumours in the thyroid gland.
Despite this pro-cancerous effect, nuclear galectin-3 has been found to have a role in promoting apoptosis in human prostate cancer cells. This suggests that the function of galectin-3 within the cell can vary depending on the cellular context and different signalling pathways involved. Furthermore, intracellular galectin-3 is also used as a marker for identifying both thyroid and prostate cancer cells which can make it a valuable tool in cancer diagnosis and research.
Extracellular Galectin-3
Outside of the cell, galectin-3 can show both inhibitory and promoting effects on apoptosis which adds to its complexity in cancer biology. One way that the extracellular galectin-3 contributes to cancer progression is by decreasing the activity of T-cells which are part of the immune system involved in recognizing and eliminating cancer cells. Galectin-3 achieved this by binding to the T-cell receptors, therefore suppressing immune responses against tumours.
In addition, extracellular galectin-3 can directly include programmed cell death in T-cells by binding to surface glycoproteins CD29 and CD7. This then triggers an apoptosis signal which leads to mitochondrial dysfunction and cell death. The inhibition of T-cell activity and induction of T-cell apoptosis can lead to tumour growth by weakening the immune system's ability to target and eliminate cells which can then in turn allow them to proliferate unchecked. In all, galectin-3 plays a crucial role in cancer biology and exhibits different effects depending on its intracellular or extracellular localization.
While it can promote cancer cell proliferation and survival in some cases, it can also induce apoptosis and regulate immune responses which highlights its potential as a therapeutic target and a diagnostic marker in cancer research and treatment.
Polygonatum Odoratum Lectin (POL)
Polygonatum Odoratum Lectin (POL) is a member of the GNA-related family of lectins, which share a common 3-dimensional structure despite the differences in the primary amino acid sequences. These lectins within this family specifically bind to the monosaccharide mannose, which can have anti-cancer properties.
In addition, POL has been known to induce apoptosis in A549 lung cancer cells while protecting healthy Human Embryonic Lung Fibroblasts (HELF) lung cells, which indicates potential tumour-suppressive effects. Treatment with POL resulted in membrane blebbing, volume reduction and DNA fragmentation in A549 cells which suggests apoptotic cell death. POL at a concentration of 23 µg/mL inhibited the proliferation of A549 cells by almost 50% after 24 hours! This inhibition of cell growth was induced through 2 main pathways
- Suppression of the Akt-NF-κb pathway: This pathway is known to promote cell survival. By suppressing this pathway, POL reduces the cell’s ability to resist cell death.
- Induction of autophagy: Autophagy is a cellular process where the cell breaks down its components for survival. However, in this case, POL appears to be inducing excessive autophagy, which leads to cell death.
- In addition, apoptosis (programmed cell death) is triggered by POL.
Similarly, in L929 murine fibrosarcoma cells, POL also demonstrated a 50% inhibitory rate at a concentration of 25 μg/mL after 24 hours. POL induces apoptosis (programmed cell death) through multiple different pathways. The caspase-dependent pathways (involves a cascade of protein activation caspases, which lead to cell disassembly), Fas-mediated apoptotic pathways (cell surface receptor when activated by POL, triggers signalling cascade which can lead to apoptosis and lastly the mitochondrial pathways (pathways which involve changes in the cells mitochondria which can lead to cell death.
Furthermore, POL enhances the effects of TNFα which stands for Tumour Necrosis Factor Alpha. TNFα is responsible for a wide range of signalling events within cells which can lead to necrosis or apoptosis in cells.
These findings suggest that POL holds promise as a potential therapeutic agent for different types of cancer by inducing apoptotic and autophagic cell death pathways.
Mistletoe (Viscum Album) Lectin
Mistletoe (Viscum album) lectin extracts have been heavily studied for their potential in cancer treatment. Certain dosages of mistletoe lectins have been shown to have pro-apoptotic effects on neoplastic cells. Studies have shown the downregulation of genes involved in glioblastoma progression and malignancy.
One example is the growth factor-β and matrix metalloproteinases which leads to the delaying of tumour growth in glioblastoma xenograft mice that followed a treatment with mistletoe extract ISCADOR. Mistletoe lectin extracts are made up of mistletoe lectin I, II and III. Research on Viscum album var. coloratum agglutinin (VCA), a lectin from Korean mistletoe has shown a positive effect on human breast cancer cells. Combining VCA with doxorubicin (DOX, a chemotherapy drug) resulted in an even stronger programmed death. The combination of VCA and DOX stimulated proteins which induce apoptosis, like Bax and Puma (p53 upregulated modulator of apoptosis) while slowing down Bcl-2 expression.
In addition, Korean mistletoe lectin causes apoptosis in p53-positive and p53-negative human liver cancer cells. The researchers also found that the lectin caused a downregulation of Bcl-2 and telomerase and an upregulation of Bax. Bax. Bcl-2 and telomerase are proteins that are involved in cell survival, while Bax is a protein that is involved in cell death. The researchers also found that the lectin also upregulated the activity of caspase-3 activation. Caspase-3 is a protein that is essential for the execution of apoptosis
Chinese mistletoe lectin-1 (CM-1) has been identified as another inducer of apoptosis in colorectal cancer cells by modulating miR-135a&b expression and up-regulating adenomatous polyposis coli (APC) gene expression. This then leads to decreased activity of the Wnt signalling pathway, which is a key pathway involved in the majority of colorectal cancer causes because it regulates β-catenin levels and subsequent gene expression.
Furthermore, mistletoe lectins have also been found to affect other cancer cell lines. Some examples are acute lymphoblastic leukemia cells (NALM-6), glioblastoma cells through natural killer (NK)-mediated cell lysis and liver cancer cells via p53 and p21 pathways.
Viscotoxins Involved in Mistletoe Therapy
Viscotoxins have a structural resemblance to plan α- and β-thionins, which are cysteine-rich and have highly basic polypeptides which can be found in the endosperm of seeds and other tissue of some gramineae plants. Vicotoxins have three disulphide bridges which are formed by six cysteine residues. These “bridges” stabilize common structures which are found in small proteins within cell membranes.
Viscotxins first start as larger preproproteins. These preproproteins have 3 important parts: a signal which tells them where to go, a thionin domain and an acidic polypeptide domain. They then go through a process to become smaller, which is to get rid of their signal. They now are called viscotoxins and help fight off harmful things that may come in.
Six viscotoxin isoforms have been identified: A1, A2, A3, B, 1-PS and U-PS. The content and composition of these viscotoxins can vary depending on the subspecies of Viscum album (host tree), the season and other factors. Viscotoxins are mostly found in seeds where they play a key role in protecting against phytopathogens. Furthermore, viscotoxins, especially viscotoxin A are found in small protein storage vacuoles in leaves and the cytoplasm. Viscotxin A3 is the most cytotoxic, whereas viscotxin B is less potent.
In one study of viscotoxins by Woynarowski and Konopa (1980) they found that these viscotoxins help stabilize DNA similar to what histones do however there were some differences. Some differences that were noticed at low concentrations were that the viscotoxins kept the DNA in organized shapes, whereas at higher concentrations, the DNA became more untidy.
In another study by Konopa et al. (1980), they found that viscotoxins were toxic to specific types of cancer cells such as KB and HeLa cells. The amount of viscotoxin which is needed to kill half of the cells is about 0.2–1.5 micrograms per millilitre. This means that in a millilitre of liquid, if you have between 02–1.5 micrograms of viscotoxins, it would kill half of the cells that it comes into contact with. However, the actual toxicity of viscotoxins could be higher because the presence of mycoplasma (contaminants in cell cultures) could have reduced the toxic side effects of viscotoxins.
In addition, scientists have noticed that viscotoxins have a certain effect on different types of white blood cells, specifically polymorphonuclear leukocytes and large granular lymphocytes. The viscotoxins can slow down the growth of these white blood cells which is called the “cytostatic effect” (A substance which slows or stops the growth of cells, including cancer cells, without actually killing them). This was seen when the extracts also had less lectin, which made the scientists think that viscotoxins may be the main reason for this effect.
The strength of this effect depends on the specific type of mistletoe plant, as different mistletoe plants have different types and amounts of viscotoxins. One example is when they tested viscotoxins on a cancer cell called Yoshida cells, these cells were affected at a concentration of 0.7 micrograms per millilitre. However, when they were tested using a lectin assay (a test to detect and measure lectins in a sample) they needed a higher concentration of 12.8 micrograms per millilitre to see an effect.
When they looked at how viscotoxins affected human white blood cells, researchers found that certain types of viscotoxins such as A1, A2, A3 and 1-PS caused the cells to die faster, changed the way the cell membrane works and also produced certain reactive molecules inside the cell.
Vicotoxins and thionins are proteins which are found in plants, and it is believed that they play a key role in protecting plants. specifically, they help protect the endosperm from microbial infections during germination. These protective functions are most likely due to their ability to be toxic to different organisms, which can disrupt the cell membrane of those who are trying to invade the plant. Proteins which are found in snake venoms are similar to viscotoxins, like cardiotoxins, cytotoxins and lytic factors which also disrupt cell membranes. These proteins have similar structures and actions at a membrane level which resemble viscotoxins.
Furthermore, studies have shown that specific structural features of these proteins are called the helical amphipathic domains. These domains have a twisty shape made up of building blocks (amino acids) in their spiral shape called a helix. This spiral has two sides. One side is attracted to water (hydrophilic) and the other side fears water (hydrophobic). Now, inside your body you have lots of water and outside cells you have water. However, the cell membrane is oily.
The helical amphipathic domain is in between these two areas. The hydrophobic side of the helix likes oily parts of the membrane whereas the hydrophilic side likes the watery parts. When protein needs to work in the membrane, the helical amphipathic domain helps keep the protein in place (anchoring). The helical amphipathic domain is stabilized by the disulfide bridges which are tiny locks which hold parts of the proteins together. These locks make sure that the helical amphipathic domain stays in its shape. Different studies have shown that these structural features are crucial for their toxic effects against plant pathogenic fungi.
Viscum Album Extracts and Immunomodulation
Mistletoe therapy, particularly with Viscum album L. (VA) extracts is commonly used together with primary treatments across Europe. VA therapy aims to improve health-related quality of life, reducing adverse events which happen during conventional cancer treatments and various immunomodulatory effects.
VA extract has many compounds (lectins, viscotoxins) which are involved in their immunomodulatory effects. Many studies have shown an increase in the number of leukocytes, granulocytes and eosinophil cells. Furthermore, VA extracts have been shown to also promote eosinophilia and increase CD4 T-lymphocytes. In addition, immune system activation has also been seen in the production of antibodies against the VA lectins and viscotoxins. VA extracts have shown an increase in cytokine levels in serum after administration to cancer patients. Subcutaneous injections of VA lectins have also triggered natural killer (NK) and T-helper cells in breast cancer patients.
Experiments in mice have shown that mistletoe lectins can act as strong immunoadjuvants, which can strengthen cellular immune responses. Furthermore, studies with lab tumour cells have shown immunomodulatory properties of Korean mistletoe lectins like the strengthening of dendritic cell maturation (a type of antigen-presenting cell which changes to allow them to activate T-cells and activates an immune response against pathogens).
In cultured glioblastoma cells, the VA extracts inhibited tumour growth and also strengthened NK cell-mediated lysis of glioblastomas which showed its potential antitumor effects. IV infusion of VA extracts has also shown many immunomodulatory effects like neutrophilia and an increase in NK cells. Additionally, VA extracts also prevented the suppression of NK cells in colorectal patients.
One immunological pathway which is involved in VA is the COX signalling pathway. COX (cyclooxygenases) are produced in response to inflammatory mediators like ROS. Traditional treatments for inflammation like nonsteroidal anti-inflammatory drugs (NSAIDs) often come with side effects because they inhibit different COX enzymes. VA has been shown to reduce COX-2 levels and exert an anti-inflammatory effect without actually interfering with physiological COX-1 activity, rather a win-win. In addition, VA has been shown to downregulate COX-2 activities, and VA reduction of COX-2 can also contribute to reducing inflammation associated with cancer-related fatigue. Unlike NSAIDs, VA anti-inflammatory mechanisms selectively target COX-2, while preserving COX-1 functions.
In conclusion, VA extracts could offer a beneficial approach to cancer treatments, especially when combined with traditional treatments.
Summary
In summary, mistletoe therapy is promising in the area of complementary and alternative medicine and offers a unique approach to cancer treatment. Mistletoe therapy not only focuses on attacking tumours but also enhancing the body's immune response. Lectins and viscotoxins not only help destroy the tumour but also enhance NK cells to help the immune system fight the cancer. Mistletoe therapy plays a key role in improving the quality of life of cancer patients and offers and holistic approach to treating cancer.
Thank you for reading! If you have any questions please email me at efata968@gmail.com
Dedicated to Richard
Sources:
https://www.cancer.gov/about-cancer/treatment/cam/hp/mistletoe-pdq
https://www.hindawi.com/journals/ecam/2019/5893017/
https://www.sciencedirect.com/science/article/pii/S266703132100021X
https://www.tandfonline.com/doi/pdf/10.1080/07060660109506966
https://www.mskcc.org/cancer-care/integrative-medicine/herbs/mistletoe-european
https://hub.jhu.edu/magazine/2014/spring/mistletoe-therapy-cancer/
