Abstract
BackgroundPrevention 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.MethodsTreatment 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.ResultsInitial 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.ConclusionsThis 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.Graphical abstract
Highlights
Prevention of metastatic invasion is one of the main challenges in the treatment of alveolar rhabdomyosarcoma
Initial screening on cell viability, migration, invasion, and colony formation To examine the anti-tumor properties of phytoestrogens on pediatric Alveolar rhabdomyosarcoma (RMA), two promising plant extracts and four single phytoestrogens as well as the positive control jasplakinolide, an actin-stabilizing compound were selected
Their anti-cancer potential was screened on the human and established RMA cell line RH-30 by cell viability assays (Fig. 1) and subsequently examined with assays to analyze the ability for cell migration, invasion and anchorage-independent colony formation (Fig. 2)
Summary
Prevention of metastatic invasion is one of the main challenges in the treatment of alveolar rhabdomyosarcoma. The two most common subtypes are the embryonal (RME; 70%) and the alveolar (RMA; 20%) rhabdomyosarcomas [4, 5]. The most frequent cause of treatment failure is local failure. Another crucial issue in treating RMS-patients is preventing and treating metastasis. The translocation positive subtypes are characterized by the expression of pax3/7-foxo fusion transcription factors which promote pathogenesis, oncogenesis and the formation of metastasis as well as drug resistance mechanism in these cancer types [2, 10,11,12,13]. Established therapies often fail in advanced RMA and tumor relapse cases, rendering novel treatment strategies necessary [1, 2]
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