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Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors Induce Oxidative Stress in Patient-Derived Glioblastoma Cells

Authors :
Ana Kostić
Sofija Jovanović Stojanov
Ana Podolski-Renić
Marija Nešović
Miodrag Dragoj
Igor Nikolić
Goran Tasić
Silvia Schenone
Milica Pešić
Jelena Dinić
Source :
Brain Sciences, Vol 11, Iss 7, p 884 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

Background: Glioblastoma (GBM) highly expresses Src tyrosine kinase involved in survival, proliferation, angiogenesis and invasiveness of tumor cells. Src activation also reduces reactive oxygen species (ROS) generation, whereas Src inhibitors are able to increase cellular ROS levels. Methods: Pro-oxidative effects of two pyrazolo[3,4-d]pyrimidine derivatives—Src tyrosine kinase inhibitors, Si306 and its prodrug pro-Si306—were investigated in human GBM cells U87 and patient-derived GBM-6. ROS production and changes in mitochondrial membrane potential were assessed by flow cytometry. The expression levels of superoxide dismutase 1 (SOD1) and 2 (SOD2) were studied by Western blot. DNA damage, cell death induction and senescence were also examined in GBM-6 cells. Results: Si306 and pro-Si306 more prominently triggered ROS production and expression of antioxidant enzymes in primary GBM cells. These effects were followed by mitochondrial membrane potential disruption, double-strand DNA breaks and senescence that eventually led to necrosis. Conclusion: Src kinase inhibitors, Si306 and pro-Si306, showed significant pro-oxidative potential in patient-derived GBM cells. This feature contributes to the already demonstrated anti-glioblastoma properties of these compounds in vitro and in vivo and encourages clinical investigations.

Details

Language :
English
ISSN :
20763425
Volume :
11
Issue :
7
Database :
Directory of Open Access Journals
Journal :
Brain Sciences
Publication Type :
Academic Journal
Accession number :
edsdoj.8b53cf626efb4386967a50026a3d49d8
Document Type :
article
Full Text :
https://doi.org/10.3390/brainsci11070884