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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
- Source :
- Cancers (Basel), Cancers, Volume 12, Issue 6, Cancers, Vol 12, Iss 1570, p 1570 (2020)
- Publication Year :
- 2020
- Publisher :
- Basel : MDPI, 2020.
-
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&ndash<br />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.
- Subjects :
- 0301 basic medicine
Cancer Research
matrix metalloproteinase
Cancer invasion
lcsh:RC254-282
Article
Extracellular matrix
Focal adhesion
Src tyrosine kinase inhibitor
03 medical and health sciences
0302 clinical medicine
In vivo
Epidermal growth factor receptor
biology
Chemistry
focal adhesion kinase
glioblastoma
Focal adhesion kinase
Glioblastoma
Matrix metalloproteinase
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
3. Good health
nervous system diseases
030104 developmental biology
Oncology
Cell culture
030220 oncology & carcinogenesis
Cancer research
biology.protein
Phosphorylation
Tyrosine kinase
cancer invasion
Proto-oncogene tyrosine-protein kinase Src
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Cancers (Basel), Cancers, Volume 12, Issue 6, Cancers, Vol 12, Iss 1570, p 1570 (2020)
- Accession number :
- edsair.doi.dedup.....c68153eccf3931c3064fbb7844ae0a5b