Viscumins functionally modulate cell motility-associated gene expression

Abstract

In Europe extracts from Viscum album L., the European white-berry mistletoe, are widely used as a complementary cancer therapy. Viscumins (mistletoe lectins, ML) have been scrutinized as important active components of mistletoe and exhibit a variety of anticancer effects such as stimulation of the immune system, induction of cytotoxicity, reduction of tumor cell motility as well as changes in the expression of genes associated with cancer development and progression. By microarray expression analysis, quantitative RT-PCR and RT-PCR based validation of microarray data we demonstrate for the Viscum album extract Iscador Qu and for the lectins Aviscumine and ML-1 that in glioma cells these drugs differentially modulate the expression of genes involved in the regulation of cell migration and invasion, including processes modulating cell architecture and cell adhesion. A variety of differentially expressed genes in ML treated cells are associated with the transforming growth factor (TGF)-β signaling pathway or are targets of TGF-β. ML treatment downregulated the expression of TGF-β itself, of the TGF-β receptor II (TGFBR2), of the TGF-β intracellular signal transducer protein SMAD2, and of matrix-metalloproteinases (MMP) MMP-2 and MMP-14. Even if the changes in gene expression differ between Aviscumine, Iscador Qu and ML-1, the overall regulation of motility associated gene expression by all drugs showed functional effects since tumor cell motility was reduced in a ML-dependent manner. Therefore, ML containing compounds might provide clinical benefit as adjuvant therapeutics in the treatment of patients with invasively growing tumors such as glioblastomas.

Preclinical Evaluation of Antitumoral and Cytotoxic Properties of Viscum album Fraxini Extract on Pediatric Tumor Cells

“…These therapies are applied for curative as well as palliative treatment concepts [4]. A widely used CAM approach of cancer patients in Europe is the administration of mistletoe (Viscum album L., Santalaceae) preparations [5]. At the beginning of the 20th century, mistletoe extracts were introduced into oncology by Rudolf Steiner, the founder of anthroposophic medicine, as a holistic and human-centered therapeutic approach [6].…”

“…At the beginning of the 20th century, mistletoe extracts were introduced into oncology by Rudolf Steiner, the founder of anthroposophic medicine, as a holistic and human-centered therapeutic approach [6]. Its antitumoral and cytotoxic properties have been investigated in different solid (e.g., urinary bladder carcinoma, glioma) and hematologic (e.g., leukemia) cancer cell lines in in vitro [5,[7][8][9][10] and in vivo experiments [11][12][13].…”

“…Mistletoe lectins I-III are reputed to be the main therapeutic relevant ingredients and have, therefore, been well studied [5]. It is assumed that mistletoe lectins act via immunostimulation by activating leucocytes [22] and have a direct effect on cancer cells by suppressing proliferation and inducing apoptosis [23][24][25].…”

Epigenetic Research in Stem Cell Bioengineering—Anti-Cancer Therapy, Regenerative and Reconstructive Medicine in Human Clinical Trials

“…In-depth study of the protective activities associated with the therapeutic potential of natural products, including spices, teas and plants, enabled the identification of key epigenetic alterations and signalling pathways by targeting specific transcription factors [111]. In fact, natural plant products showed immunomodulatory activity acting as anti-oxidant and anti-tumour agents-for example, Viscum album L. extracts were observed to downregulate TGF-β, providing clinical benefits to subjects affected by invasive tumours [112]. Moreover, clues concerning epigenetic mechanisms, with potential in regenerative therapies, are partially drawn from epigenetic reprogramming processes required for the development of an embryo from fertilized egg and the establishment of the totipotency of cells in vivo [113].…”

Prospect of natural products in glioma: A novel avenue in glioma management

“…Viscumins is the active component found in mistletoe, which induces cytotoxicity along with stimulation of the immune responses. It also prevents cell migration and invasion by modulating different gene expressions such as TGF‐β, TGFBR2, SMAD2, MMP‐2, and MMP‐14 in LNT‐229 cells (Schötterl et al, ).…”