European Mistletoe (Viscum album) Extract Is Cytotoxic to Canine High-Grade Astrocytoma Cells In Vitro and Has Additive Effects with Mebendazole

Malignant gliomas are associated with extremely poor clinical outcomes in both humans and dogs, and novel therapies are needed. Glioma-bearing canine patients may serve as promising preclinical models for human therapies, including complementary medicine. The objective of this study was to evaluate the effects of mistletoe extract (Viscum album) alone and in combination with mebendazole in an in vitro model of canine high-grade astrocytoma using the cell line SDT-3G. SDT-3G cells were exposed to a range of concentrations of mistletoe extract alone to obtain an IC50. In separate experiments, cells were exposed to mebendazole at a previously determined IC50 (0.03 µM) alone or in conjunction with varying concentrations of mistletoe extract to determine the additive effects. The IC50 for mistletoe alone was 5.644 ± 0.09 SD μg/mL. The addition of mistletoe at 5 μg/mL to mebendazole at 0.03 µM led to increased cell death compared to what would be expected for each drug separately. The cytotoxicity of mistletoe in vitro and its additive effect with mebendazole support future expanded in vitro and in vivo studies in dogs and supply early evidence that this may be a useful adjunct therapeutic agent for use in glioma-bearing dogs. To the authors’ knowledge, this is the first published report of Viscum album extract in canine glioma.

Investigation of force-like effects of potentized preparations

The scope of this project is the investigation of the possible occurrence of force-like effects of potentized preparations. Based on earlier work [1, 2] we have chosen two preclinical models: a droplet evaporation method applied on wheat seeds and a bioassay with cress stressed with colchicine. In both methods we investigate if potentized and not potentized substances exhibit force-like effects. We study two types of potentization procedures. First we study classical homeopathic potentization (Natrium muriaticum 30cH) and compare it with unpotentized NaCl 0.9%. Second, we study anthroposophic potentization (Iscador, mistletoe (Viscum album L.) extracts treated with a special mechanized pharmaceutical process) and compare it with unpotentized mistletoe extract (not mechanically treated). Droplet evaporation method is performed as described in detail elsewhere [1]. In short: wheat seeds were placed in the inner space of bilayer recipients, whereas, in the outer space (i) the unpotentized substance, (ii) the potentized substance, or (iii) a water control is placed. After one week wheat seeds are removed from the recipients and placed in water for 1h. Droplets of the obtained leakage were evaporated on glass-slides in controlled conditions. The droplet residues are photographed in magnification 100x and analyzed for fractal dimension. Cress growth test is performed as described in detail elsewhere [2]. For the study of force-like effects, ampoules of the above mentioned substances and ampoules of water for injection are placed for 2 days in recipients filled with purified water. Subsequently 20 µg/ml colchicine were added. The so prepared water is used to grow selected cress seeds in bags for 4 days. The plants grow in darkness under controlled conditions and show a morphological malformation due to the colchicine. The length of the root and shoot at each plant is measured and the root/shoot ratio is calculated, to determine if there is any difference between the treatments. 1. Kokornaczyk, M.O., S. Baumgartner, and L. Betti, Preliminary study on force-like effects between As45x, water, and wheat seeds performed by means of the droplet evaporation method. International Journal of High Dilution Research, 2015. 14(2): p. 17-19. 2. Baumgartner S, Flückiger H, Kunz M, Scherr C, Urech K. Evaluation of Preclinical Assays to Investigate an Anthroposophic Pharmaceutical Process Applied to Mistletoe (Viscum album L.) Extracts. Evid Based Complement Alternat Med. 2014: Article ID 620974.

The Potential Role of Korean Mistletoe Extract as an Anti-Inflammatory Supplementation

Korean mistletoe has anti-inflammatory and antioxidant functions and may be a useful training supplement. We investigated the effect of Korean mistletoe extract (KME) on inflammatory markers after high-intensity exercise by 20 university male rowers (KME group vs. CON group) consuming 110 mL KME/dose (2 times a day over 8 weeks). Blood samples were collected for measurement of serum cytokine levels at baseline, immediately after exercise, and following 30 minutes of recovery. Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP) were used as markers for inflammation. After supplementation, IL-6 and TNF-α levels were significantly lowered in the KME group than in the CON group at baseline, immediately after exercise, and following 30 minutes of recovery. KME can reduce high-strength exercise-induced increases in the levels of serum inflammatory cytokines in active individuals and improve anti-inflammatory functions.

Effect of mistletoe extract on tumor response in neoadjuvant chemoradiotherapy for rectal cancer: a cohort study

Background Mistletoe extract, used as a complementary chemotherapeutic agent for cancer patients, has anticancer effects against various malignancies. The aim of the present study was to evaluate the effect of mistletoe extract (Abnoba Viscum Q®) on tumor responses to neoadjuvant chemoradiotherapy (NCRT) for locally advanced rectal cancer. Methods This study included patients with rectal cancer who underwent NCRT between January 2018 and July 2020. In the mistletoe group (MG), the patients were administered Abnoba Viscum Q® subcutaneously during chemoradiotherapy—maintained just before surgery. Patient demographics, clinical outcomes, histopathological outcomes, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) assay results were compared between the MG and non-mistletoe group (NMG). Two rectal cancer cell lines (SNU-503 and SNU-503R80Gy) were treated with Abnoba Viscum Q® to assess its mechanistic effects in vivo. Results Overall, the study included 52 patients (MG: n = 15; NMG: n = 37). Baseline demographics between the two groups were similar, except carbohydrate antigen 19-9 levels and tumor location from the anal verge. There was no difference in the clinical stage between the two groups. A better tumor response in the MG, relative to the NMG, was observed with respect to tumor regression grade (TRG), T stage, and overall tumor–node–metastasis stage. Tumor response was significantly better in the MG than in the NMG in terms of pathologic complete response rate (53.3% vs. 21.6%, P = 0.044), good TRG response (66.7% vs. 32.4%, P = 0.024), T downstaging (86.7% vs. 43.2%, P = 0.004), and overall downstaging (86.7% vs. 56.8%, P = 0.040). The toxicities during NCRT were minimal in both groups. More apoptotic cells were noted in MG samples than in the NMG samples on TUNEL staining. Cleaved caspase-3 level following treatment with Abnoba Viscum Q® was higher in SNU-503R80Gy cells than in SNU-503 cells. Conclusion Patients treated with chemoradiation combined with mistletoe extract showed better outcomes than patients not treated with mistletoe extract in terms of tumor responses. This diversity in treatment may improve the efficacy of NCRT, leading to better oncologic outcomes. Prospective and randomized studies with long-term follow-up are warranted to confirm and extend these results.

The effect of mistletoe extract on tumor response in neoadjuvant chemoradiotherapy for rectal cancer

Background Mistletoe extract, which is usually used as a complementary agent for cancer patients, provides an anticancer effect on various malignancies. The present study aimed to evaluate the effect of mistletoe extract (Abnoba Viscum Q®) on tumor responses in neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Methods The rectal cancer patients who underwent neoadjuvant chemoradiotherapy were analyzed from Jan 2018 to Jul 2020. In the mistletoe group (MG), the patients were administered Abnoba Viscum Q® subcutaneously during chemoradiotherapy, and it was maintained just before surgery. Patients' demographics, clinical outcomes, and histopathological outcomes were compared between chemoradiation with the MG and nonmistletoe group (NMG). Results A total of 52 patients were included. There were MG of 15 patients and NMG of 37 patients. Baseline demographics were statistically similar between the two groups except the CA19-9 and tumor location levels from anal verge. There was no difference in the clinical stage for both groups. We also observed better tumor response in MG in terms of TRG, T stage, and overall TNM stage. Tumor response was significantly better in MG comparing NMG in terms of pathologic complete response rate (53.3% vs 21.6%, p = 0.044), good responder of tumor regression grade (66.7% vs 32.4%, p = 0.024), T downstaging (86.7% vs 43.2%, p = 0.004), and overall downstaging (86.7% vs 56.8%, p = 0.040). The toxicities during NCRT in both groups were minimal. Conclusion MG treated with chemoradiation combined with mistletoe extract showed better outcomes than NMG in terms of tumor responses. This diversity in treatment may elevate the method to hope for better oncologic outcomes. Prospective and randomized studies with long-term follow-up are warranted to confirm and extend this study.

Mistletoe Extract Viscum Fraxini-2 for Treatment of Advanced Hepatocellular Carcinoma: A Case Series

Background: Hepatocellular carcinoma (HCC) is the fourth leading cause of death from cancer worldwide, and for advanced HCC the prognosis is poor. Preliminary studies indicate mistletoe extracts may have anticancer activity for HCC. Methods: A prospective observational case series of advanced HCC patients that chose to take a mistletoe extract called viscum fraxini-2 (VF-2) alone for treatment. Time on treatment, imaging, and laboratory values were collected for descriptive analyses. Results: A total of 12 patients with advanced HCC enrolled onto the protocol, and 10 patients had data available for evaluation. The majority were male (10/12) with a median age of 64 (SD 11). Most patients had received sorafenib therapy (9/12) and had varying Child-Pugh classes (A-4, B-6, C-2). Treatment with VF-2 ranged from 1 to 36 weeks with a mean of 12.3 weeks (SD 12). Six patients received 8 weeks of treatment, and 3 patients received 12 or more weeks of treatment. For patients that received at least 4 weeks of treatment, the average AFP value stabilized during the first 4 weeks of treatment. Two patients experienced an AFP decrease of >30%, approximately 37 and 40% decreases at the nadir. One patient had stable disease of 9 months. Major side effects were fever, fatigue, rash, and local injection site reaction of swelling, redness, and tenderness. Conclusion: This case series of advanced HCC indicates that mistletoe extract VF-2 may have potential biological activity against HCC for selected patients. Research is needed to identify the active compound and predictive markers of response.

Mistletoe Extract Targets the STAT3-FOXM1 Pathway to Induce Apoptosis and Inhibits Metastasis in Breast Cancer Cells

Mistletoe extracts (Viscum album L.) have been widely used as complementary and alternative medicines for the treatment of cancer, and their cytotoxic effects have been reported on various types of cancer. However, the molecular targets of mistletoe extracts have not been well studied. Herein, we investigated molecules associated with the in vitro and in vivo anticancer effects of mistletoe extract using 4T1 murine breast cancer cells. Mistletoe extract induced apoptosis and inhibited the signal transducer and activator of transcription3 (STAT3) phosphorylation. This inhibition was accompanied by the downregulations of forkhead box M1 (FOXM1) and the DNA repair proteins, RAD51 and survivin. Mistletoe extract simultaneously increased the expression of the DNA damage marker proteins, phosphorylated H2A histone family member X (H2A.X), and phosphorylated p38. Furthermore, mistletoe extract effectively suppressed tumor growth in 4T1 tumor-bearing BALB/c mice. In addition to tumor growth inhibition, mistletoe extract inhibited lung metastasis in the tumor-bearing mice and cell invasiveness by downregulating the expressions of matrix metalloproteinases (MMPs), urokinase-type plasminogen activator (uPA), uPA receptor, and markers of epithelial-mesenchymal transition (snail and fibronectin). Taken together, our results suggest that mistletoe extract targets the STAT3-FOXM1 pathway for its cytotoxic effects, and that mistletoe extracts might be useful for the treatment of patients with cancers highly expressing the STAT3-FOXM1 pathway.