Open Access

Background: Prevention of metastatic invasion is one of the main challenges in the treatment of alveolar rhabdomyosarcoma. Still the therapeutic options are limited. Therefore, an anti-tumor screening was initiated focusing on the anti-metastatic and anti-invasion properties of selected medicinal plant extracts and phytoestrogens, already known to be effective in the prevention and treatment of different cancer entities. Methods: Treatment effects were first evaluated by cell viability, migration, invasion, and colony forming assays on the alveolar rhabdomyosarcoma cell line RH-30 in comparison with healthy primary cells. Results: Initial anti-tumor screenings of all substances analyzed in this study, identified the plant extract of Vincetoxicum arnottianum (VSM) as the most promising candidate, harboring the highest anti-metastatic potential. Those significant anti-motility properties were proven by a reduced ability for migration (60%), invasion (99%) and colony formation (61%) under 48 h exposure to 25 μg/ml VSM. The restricted motility features were due to an induction of the stabilization of the cytoskeleton – actin fibers were 2.5-fold longer and were spanning the entire cell. Decreased proliferation (PCNA, AMT, GCSH) and altered metastasis (e. g. SGPL1, CXCR4, stathmin) marker expression on transcript and protein level confirmed the significant lowered tumorigenicity under VSM treatment. Finally, significant alterations in the cell metabolism were detected for 25 metabolites, with levels of uracil, N-acetyl serine and propanoyl phosphate harboring the greatest alterations. Compared to the conventional therapy with cisplatin, VSM treated cells demonstrated a similar metabolic shutdown of the primary cell metabolism. Primary control cells were not affected by the VSM treatment. Conclusions: This study revealed the VSM root extract as a potential, new migrastatic drug candidate for the putative treatment of pediatric alveolar rhabdomyosarcoma with actin filament stabilizing properties and accompanied by a marginal effect on the vitality of primary cells.

Ethnopharmacological relevance: Berberis orthobotrys (BORM) is a medical plant with a long history in traditional usage for the treatment of wounds, cancer, gastrointestinal malady and several other diseases. Our previous studies identified the endemic Pakistani plant Berberis orthobotrys Bien. ex Aitch. as promising source for the treatment of breast cancer and osteosarcoma. Aim of the study: The present study was aimed to evaluate the anti-cancer properties of 26 plant derived extracts and compounds including the methanolic root extract of Berberis orthobotrys (BORM) on pediatric alveolar rhabdomyosarcoma (RMA), which is known to develop drug resistance, metastatic invasion and potential Tumor progression. Materials and methods: The main anti-tumor activity of BORM was verified by focusing on morphological, cell structural and metabolic alterations via metabolic profiling, cell viability measurements, flow cytometry, western blotting and diverse microscopy-based methods using the human RMA cell line Rh30. Results: Exposure of 25 μg/ml BORM exerts an influence on the cell stability, the degradation of oncosomes as well as the shutdown of the metabolic activity of RMA cells, primarily by downregulation of the energy metabolism. Therefore glycyl-aspartic acid and N-acetyl serine decreased moderately, and uracil increased intracellularly. On healthy, non-transformed muscle cells BORM revealed very low metabolic alterations and nearly no cytotoxic impact. Furthermore, BORM is also capable to reduce Rh30 cell migration (~50%) and proliferation (induced G2/M cycle arrest) as well as to initiate apoptosis confirmed by reduced Bcl-2, Bax and PCNA expression and induced PARP-1 cleavage. Conclusions: The study provides the first evidence, that BORM treatment is effective against RMA cells with low side effects on healthy cells.

In a long-term research strategy, the German higher federal authorities responsible for human and environmental safety – the German Environment Agency (UBA), the Federal Institute for Risk Assessment (BfR), the Federal Institute for Occupational Safety and Health (BAuA), the Federal Institute for Materials Research and Testing (BAM) and the National Metrology Institute (PTB) – are accompanying the rapid pace of development of new materials from the points of view of occupational safety and health, consumer protection and environmental protection. The strategy is therefore closely linked with public funding programmes for research on nanomaterials and other advanced materials, such as those of the Federal Ministry of Education and Research (BMBF) (“From Material to Innovation”) and the EU (“Horizon 2020”). The research strategy builds on the outcomes so far of the joint research strategy of the higher federal authorities launched in 2008 and first evaluated in 2013, “Nanotechnology: Health and Environmental Risks of Nanomaterials”, while additionally covering other advanced materials where these pose similar risks to humans and the environment or where such risks need to be studied. It also takes up the idea of application safety of chemical products from the New Quality of Work (INQA) initiative of the Federal Ministry of Labour and Social Affairs (BMAS) and the concept of sustainable chemistry endorsed by the Federal Ministry for the Environment, Nature Conservation, Building and Nuclear Safety (BMUB). Application safety and environmental compatibility are aimed for advanced materials and derived products in order to largely rule out unacceptable risks to humans and the environment. This can be achieved by: 1. Using safe materials without hazardous properties for humans and the environment direct application safety); or 2. Product design for low emissions and environmental compatibility over the entire product lifecycle (integrated application safety); or 3. Product stewardship, where producers support users in taking technical, organisational and personal safety measures for the safe use and disposal of products (supported application safety). As a comprising part of the Federal Government’s Nanotechnology Action Plan 2020, the update of the joint research strategy aims to contribute to governmental research in the following main areas: • Characterising and assessing the human and environmental risks of advanced materials • Supporting research institutions and business enterprises • Science-based revision of legal requirements and recommendations • Public acceptance The research strategy is to be implemented in projects and other research-related activities. These include governmental research, tendering and extramural research funding, and participation in mostly publicly supported projects with third-party funding. Additional activities will take place as part of policy advice and the ongoing work of the sovereign tasks of agencies involved. Interdisciplinary and transdisciplinary approaches will be used to better connect risk and safety research with innovation research and material development. In keeping up with the rapid pace of development, the time horizon for the research strategy is up to 2020. The research objectives address the research approaches likely to be actionable in this period. The research strategy will be supported by a working group and be evaluated and revised by the end of the Nanotechnology Action Plan 2020.