Article

Molecular mechanisms of mistletoe plant extract-induced apoptosis in acute lymphoblastic leukemia in vivo and in vitro

Department of Pediatric Oncology/Hematology, Otto-Heubner-Center for Pediatric and Adolescent Medicine, Charité, Universitätsmedizin Berlin, Germany.
Cancer Letters (Impact Factor: 5.62). 07/2008; 264(2):218-28. DOI: 10.1016/j.canlet.2008.01.036
Source: PubMed

ABSTRACT

Viscum album (Mistletoe) is one of the most widely used alternative cancer therapies. Aqueous mistletoe extracts (MT) contain the three mistletoe lectins I, II and III as one predominant group of biologically active agents. Although MT is widely used, there is a lack of scientifically sound preclinical and clinical data. In this paper, we describe for the first time the in vivo efficacy and mechanism of action of MT in lymphoblastic leukemia. For this purpose, we first investigated both the cytotoxic effect and the mechanism of action of two standardized aqueous MTs (MT obtained from fir trees (MT-A); MT obtained from pine trees (MT-P)) in a human acute lymphoblastic leukemia (ALL) cell line (NALM-6). MT-A, MT-P and ML-I inhibited cell proliferation as determined by Casy Count analysis at very low concentrations with MT-P being the most cytotoxic extract. DNA-fragmentation assays indicated that dose-dependent induction of apoptosis was the main mechanism of cell death. Finally, we evaluated the efficacy of MT-A and MT-P in an in vivo SCID-model of pre-B ALL (NALM-6). Both MTs significantly improved survival (up to 55.4 days) at all tested concentrations in contrast to controls (34.6 days) without side effects.

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    • "Accordingly, several plant lectins have been widely studied and were found to possess different tumor suppressive activities that are associated with a potent anticancer response25,28,31. For example, mistletoe lectins belonging to the RIP II family have been shown to inhibit lymphoma growth in mice and are used as an adjuvant therapy to treat various forms of human cancers40. Therefore, the results of this study support the use of AGG as a naturally occurring anticancer molecule for liver cancer treatment. Further insight into the molecular mechanisms involved in the apoptotic machinery will help us gain knowledge regarding the antineoplastic efficacy of AGG. "
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    ABSTRACT: Aim: Abrus agglutinin (AGG) from the seeds of Indian medicinal plant Abrus precatorius belongs to the class II ribosome inactivating protein family. In this study we investigated the anticancer effects of AGG against human hepatocellular carcinoma in vitro and in vivo. Methods: Cell proliferation, DNA fragmentation, Annexin V binding, immunocytofluorescence, Western blotting, caspase activity assays and luciferase assays were performed to evaluate AGG in human liver cancer cells HepG2. Immunohistochemical staining and TUNEL expression were studied in tumor samples of HepG2-xenografted nude mice. Results: AGG induced apoptosis in HepG2 cells in a dose- and time-dependent manner. AGG-treated HepG2 cells demonstrated an increase in caspase 3/7, 8 and 9 activities and a sharp decrease in the Bcl-2/Bax ratio, indicating activation of a caspase cascade. Co-treatment of HepG2 cells with AGG and a caspase inhibitor or treatment of AGG in Bax knockout HepG2 cells decreased the caspase 3/7 activity in comparison to HepG2 cells exposed only to AGG. Moreover, AGG decreased the expression of Hsp90 and suppressed Akt phosphorylation and NF-κB expression in HepG2 cells. Finally, AGG treatment significantly reduced tumor growth in nude mice bearing HepG2 xenografts, increased TUNEL expression and decreased CD-31 and Ki-67 expression compared to levels observed in the untreated control mice bearing HepG2 cells. Conclusion: AGG inhibits the growth and progression of HepG2 cells by inducing caspase-mediated cell death. The agglutinin could be an alternative natural remedy for the treatment of human hepatocellular carcinomas.
    Full-text · Article · May 2014 · Acta Pharmacologica Sinica
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    • "In 2003 more than 18 million defined daily doses were prescribed in Germany [4]. Mistletoe extracts have been shown to kill cancer cells in vitro and can stimulate immune system cells both in vitro and in vivo [5] [6] [7]. Two components of mistletoe, namely, viscotoxins and lectins, have been shown to be largely responsible for these effects [7] [8] [9]. "
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    ABSTRACT: Background. In Europe, mistletoe extracts are widely used as a complementary cancer therapy. We assessed the safety of subcutaneous mistletoe as a conjunctive therapy in cancer patients within an anthroposophic medicine setting in Germany. Methods. A multicentre, observational study was performed within the Network Oncology. Suspected mistletoe adverse drug reactions (ADRs) were described by frequency, causality, severity, and seriousness. Potential risk factors, dose relationships and drug-drug interactions were investigated. Results. Of 1923 cancer patients treated with subcutaneous mistletoe extracts, 283 patients (14.7%) reported 427 expected effects (local reactions <5 cm and increased body temperature <38°C). ADRs were documented in 162 (8.4%) patients who reported a total of 264 events. ADRs were mild (50.8%), moderate (45.1%), or severe (4.2%). All were nonserious. Logistic regression analysis revealed that expected effects were more common in females, while immunoreactivity decreased with increasing age and tumour stage. No risk factors were identified for ADRs. ADR frequency increased as mistletoe dose increased, while fewer ADRs occurred during mistletoe therapy received concurrent with conventional therapies. Conclusion. The results of this study indicate that mistletoe therapy is safe. ADRs were mostly mild to moderate in intensity and appear to be dose-related and explained by the immune-stimulating, pharmacological activity of mistletoe.
    Full-text · Article · Jan 2014 · Evidence-based Complementary and Alternative Medicine
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    • "In 2003 more than 18 million defined daily doses were prescribed in Germany [4]. Mistletoe extracts have been shown to kill cancer cells in vitro and can stimulate immune system cells both in vitro and in vivo [5] [6] [7]. Two components of mistletoe, namely, viscotoxins and lectins, have been shown to be largely responsible for these effects [7] [8] [9]. "

    Full-text · Conference Paper · Sep 2013
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