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
2020
Autori:
Nešović, MarijaDivac Rankov, Aleksandra
Podolski-Renić, Ana
Nikolić, Igor
Tasić, Goran
Mancini, Arianna
Schenone, Silvia
Pešić, Milica
Dinić, Jelena
Tip dokumenta:
Članak u časopisu (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt:
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.
Ključne reči:
Src tyrosine kinase inhibitor; Cancer invasion; Focal adhesion kinase; Glioblastoma; Matrix metalloproteinaseIzvor:
Cancers (Basel), 2020, 12, 6, 1570-Finansiranje / projekti:
- Identifikacija molekularnih markera za predikciju progresije tumora, odgovora na terapiju i ishoda bolesti (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41031)
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200007 (Univerzitet u Beogradu, Institut za biološka istraživanja 'Siniša Stanković') (RS-MESTD-inst-2020-200007)
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200042 (Univerzitet u Beogradu, Institut za molekularnu genetiku i genetičko inženjerstvo) (RS-MESTD-inst-2020-200042)
- Kompleksne bolesti kao model sistem za proučavanje modulacije fenotipa-strukturna i funkcionalna analiza molekularnih biomarkera (RS-MESTD-Basic Research (BR or ON)-173008)
DOI: 10.3390/cancers12061570
ISSN: 2072-6694
PubMed: 32545852