2. Academic Validation
  3. 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

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

  • Cancers (Basel). 2020 Jun 14;12(6):1570. doi: 10.3390/cancers12061570.
Marija Nešović 1,  Aleksandra Divac Rankov 2,  Ana Podolski-Renić 1,  Igor Nikolić 3 4,  Goran Tasić 3 4,  Arianna Mancini 5 6,  Silvia Schenone 7,  Milica Pešić 1,  Jelena Dinić 1
Affiliations

Affiliations

  • 1 Department of Neurobiology, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia.
  • 2 Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia.
  • 3 Clinic for Neurosurgery, Clinical Center of Serbia, Pasterova 2, 11000 Belgrade, Serbia.
  • 4 School of Medicine, University of Belgrade, Doktora Subotića 8, 11000 Belgrade, Serbia.
  • 5 Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
  • 6 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via A. Moro 2, I-53100 Siena, Italy.
  • 7 Department of Pharmacy, University of Genova, Viale Benedetto XV 3, 16132 Genova, Italy.
PMID: 32545852 DOI: 10.3390/cancers12061570
Abstract

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.

Keywords

Src tyrosine kinase inhibitor; cancer invasion; focal adhesion kinase; glioblastoma; matrix metalloproteinase.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-164527
    Src抑制剂
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