Src Inhibitors Pyrazolo[3,4-d]pyrimidines, Si306 and Pro-Si306, Inhibit Focal Adhesion Kinase and Suppress Human Glioblastoma Invasion In Vitro and In Vivo

Glioblastoma (GBM), as the most aggressive brain tumor, displays a high expression of Src tyrosine kinase, which is involved in the survival, migration, and invasiveness of tumor cells. Thus, Src emerged as a potential target for GBM therapy. The effects of Src inhibitors pyrazolo[3,4-d]pyrimidines, Si306 and its prodrug pro-Si306 were investigated in human GBM cell lines (U87 and U87-TxR) and three primary GBM cell cultures. Primary GBM cells were more resistant to Si306 and pro-Si306 according to the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. However, the ability of all GBM cells to degrade the extracellular matrix was considerably compromised after Si306 and pro-Si306 applications. Besides reducing the phosphorylation of Src and its downstream signaling pathway components, both compounds decreased the phosphorylated form of focal adhesion kinase (FAK) and epidermal growth factor receptor (EGFR) expression, showing the potential to suppress the aggressiveness of GBM. In vivo, Si306 and pro-Si306 displayed an anti-invasive effect against U87 xenografts in the zebrafish embryo model. Considering that Si306 and pro-Si306 are able to cross the blood-brain barrier and suppress the spread of GBM cells, we anticipate their clinical testing in the near future. Moreover, the prodrug showed similar efficacy to the drug, implying the rationality of its use in clinical settings

Effects of vanadate on the mycelium of edible fungus Coprinus comatus

Vanadate is proposed to play a pivotal role in application of edible fungus Coprinus comatus for medical purposes. In this study the concentration of extracellular vanadate acceptable for the submerged cultivation of C. comatus mycelium was established. The mycelium could grow, and overcome vanadate toxic effects, up to the concentration of 3.3 mM. Moreover, in this condition, at the end of the exponential phase of growth, biomass yield was almost identical to that in the control. P-31 NMR spectroscopy showed that addition of 10 mM vanadate to the mycelium in the exponential phase of growth provoked instantaneous increase of a sugar phosphates level which could be related to changes in activities of glycolytic enzymes. Exposure to higher vanadate concentration was toxic for the cell. V-51 NMR measurements revealed that monomer of vanadate is present in the cytoplasm causing the metabolic changes. C. comatus has also capacity for vanadate reduction, as shown by EPR measurements, but vanadyl uptake is significantly less comparing to vanadate