Glioblastoma multiforme is the most aggressive primary brain tumour. At the cellular and molecular levels, several mechanisms responsible for apoptosis or autophagy induction are blocked. Identification of molecular targets stimulating cells to initiate programmed cell death should be performed for therapeutic purposes. A promising solution is the combination of temozolomide and quercetin. The aim of our study was to evaluate the effect of both drugs, applied alone and in combinations, on apoptosis and autophagy induction in human glioblastoma multiforme T98G cells. Our results clearly indicate that quercetin and temozolomide induce apoptosis very significantly, having no effect on autophagy induction. At the molecular level, it was correlated with caspase 3 and 9 activation, cytochrome c release from the mitochondrium and a decrease in the mitochondrial membrane potential. Both drugs are also potent Hsp27 and Hsp72 inhibitors. This suggests that the apoptotic signal goes through an internal pathway. Increased expression of caspase 12 and the presence of several granules in the cytoplasm after temozolomide treatment with or without quercetin preceding appearance of apoptosis may suggest that apoptosis is initiated by ER stress. Additionally, it was accompanied by changes in the nuclear morphology from circular to ‘croissant like’.
The aim of the present study was to investigate the effect of sorafenib and quercetin on the induction of apoptosis and autophagy in human anaplastic astrocytoma (MOGGCCM) and glioblastoma multiforme (T98G) cell lines. In MOGGCCM cells, sorafenib initiated mainly apoptosis, mediated by the mitochondrial pathway with mitochondrial membrane permeabilization, cytochrome c release to the cytoplasm, and activation of caspase 9 and 3. Additional incubation with quercetin potentiated the pro-apoptotic properties of sorafenib. In T98G cells, autophagy was observed most frequently after the sorafenib treatment. It was accompanied by increased beclin 1 and LC3II expression. Administration of quercetin after the sorafenib treatment resulted in an increased number of autophagic cells. After simultaneous drug application, the level of autophagy was lower in favour of apoptosis. Inhibition of heat shock proteins expression by specific small interfering RNA significantly increased the sensitivity of both the cell lines to induction of apoptosis, but not autophagy. We demonstrated for the first time that sorafenib and quercetin are very effective programmed cell death inducers in T98G and MOGGCCM cells, especially in cells with blocked expression of heat shock proteins.
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