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.
Highlights
Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor, classified by theWorld Health Organization (WHO) as grade IV [1,2]
The sensitivity of primary GBM cell cultures to Si306, pro-Si306, and the well-known SFK inhibitor dasatinib after 72 h treatment was assessed by the MTT assay and compared to the results we previously obtained in U87 and U87-TxR cell lines (Table 1) [28]
Our results showed that primary GBM cells are less sensitive to Src tyrosine kinase inhibitors (STKIs) compared to GBM cell lines U87 and U87-TxR, which may reflect the differences in the expression levels of the target molecule
Summary
Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor, classified by theWorld Health Organization (WHO) as grade IV [1,2]. Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor, classified by the. The invasion and migration of GBM cells into normal brain tissue is among the main reasons for unsuccessful GBM treatment [5,6]. Even with current treatment against GBM, lethal relapses usually occur with more aggressive and resistant behavior [9]. GBM relapses at places distant from its primary site, implying that its cells are spread throughout the brain parenchyma before surgical resection of the tumor is performed [11]. It is reasonable to consider neoadjuvant therapy which would suppress the GBM invasion before surgery. This type of approach is common for other malignancies such as lung carcinoma [12]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
