Kostić Ana, Jovanović Stojanov Sofija, Podolski-Renić Ana, Nešović Marija, Dragoj Miodrag, Nikolić Igor, Tasić Goran, Schenone Silvia, Pešić Milica, Dinić Jelena
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.
Clinic for Neurosurgery, Clinical Center of Serbia, Pasterova 2, 11000 Belgrade, Serbia.
Brain Sci. 2021 Jun 30;11(7):884. doi: 10.3390/brainsci11070884.
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.
Pro-oxidative effects of two pyrazolo[3,4-]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.
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.
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.
胶质母细胞瘤（GBM）高表达参与肿瘤细胞存活、增殖、血管生成和侵袭的Src酪氨酸激酶。Src激活还会减少活性氧（ROS）的产生，而Src抑制剂能够增加细胞内ROS水平。
研究了两种吡唑并[3,4-]嘧啶衍生物——Src酪氨酸激酶抑制剂Si306及其前药pro-Si306在人GBM细胞U87和患者来源的GBM-6中的促氧化作用。通过流式细胞术评估ROS产生和线粒体膜电位的变化。通过蛋白质印迹法研究超氧化物歧化酶1（SOD1）和2（SOD2）的表达水平。还在GBM-6细胞中检测了DNA损伤、细胞死亡诱导和衰老情况。
Si306和pro-Si306更显著地触发了原发性GBM细胞中ROS的产生和抗氧化酶的表达。这些作用随后导致线粒体膜电位破坏、双链DNA断裂和衰老，最终导致坏死。
Src激酶抑制剂Si306和pro-Si306在患者来源的GBM细胞中显示出显著的促氧化潜力。这一特性有助于这些化合物在体外和体内已被证明的抗胶质母细胞瘤特性，并鼓励进行临床研究。
