Search

The verified presence of a glioblastoma multiforme (GBM) tumor in the motor area of the brain, in a patient lacking preoperative neurological deficit, offers no certainty that the tumor can be radically removed without the possibility of causing postoperative motor deficit. We present a series of 60 patients hospitalized at the Clinical Department of Neurosurgery, Clinical Center of Serbia in Belgrade between October 2011 and February 2015, harboring tumors located within and in the vicinity of the motor zone of the brain. By using Karnofsky's index (KI), the pre- and postoperative conditions of the patients were evaluated. Regarding electrical stimulation of the motor cortex, significantly lower values of the electrical current intensity, frequency, and pulse wave duration (p < 0.01) were needed for triggering motor response in case of GBM tumor compared to a slowly growing tumor (low-grade). Patients with low-grade gliomas (LGG) had statistically significantly higher KI values pre- and postoperatively than patients with GBM (p < 0.01). Using electrical stimulation of the cortex, a higher grade of resection of LGG could be achieved as compared with the group presenting with GBM (χ² = 5.281; df = 1; p < 0.05). Our findings and review of the results reported by other authors underline the necessity of routine application of electrical stimulation of the cerebral cortex in order to identify the primary motor field (M1).

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]