An Interplay between Senescence, Apoptosis and Autophagy in Glioblastoma Multiforme—Role in Pathogenesis and Therapeutic Perspective

Abstract

Autophagy, cellular senescence, programmed cell death and necrosis are key responses of a cell facing a stress. These effects are partly interconnected, but regulation of their mutual interactions is not completely clear. That regulation seems to be especially important in cancer cells, which have their own program of development and demand more nutrition and energy than normal cells. Glioblastoma multiforme (GBM) belongs to the most aggressive and most difficult to cure cancers, so studies on its pathogenesis and new therapeutic strategies are justified. Using an animal model, it was shown that autophagy is required for GBM development. Temozolomide (TMZ) is the key drug in GBM chemotherapy and it was reported to induce senescence, autophagy and apoptosis in GBM. In some GBM cells, TMZ induces small toxicity despite its significant concentration and GBM cells can be intrinsically resistant to apoptosis. Resveratrol, a natural compound, was shown to potentiate anticancer effect of TMZ in GBM cells through the abrogation G2-arrest and mitotic catastrophe resulting in senescence of GBM cells. Autophagy is the key player in TMZ resistance in GBM. TMZ can induce apoptosis due to selective inhibition of autophagy, in which autophagic vehicles accumulate as their fusion with lysosomes is blocked. Modulation of autophagic action of TMZ with autophagy inhibitors can result in opposite outcomes, depending on the step targeted in autophagic flux. Studies on relationships between senescence, autophagy and apoptosis can open new therapeutic perspectives in GBM.

Quinoline‐Conjugated Ruthenacarboranes: Toward Hybrid Drugs with a Dual Mode of Action

“…LN229 was used as model for aggressive, autophagy‐prone malignant GBM, whereas MCF‐7 was selected for consistency with our previous studies . We aimed at supporting the observations made from in vitro colorimetric assays, concerning the effects of the conjugation with a quinoline residue of the ruthenacarborane fragment on proliferation, survival and death mechanisms of the selected cell lines.…”

“…Thus, 4 acts in vitro as a hybrid molecule against malignant glioblastoma cells (LN229), inhibiting cellular division and, in parallel, cytoprotective autophagy, which supports the rational drug design idea of this work. It is obvious from the recent literature that modulation of autophagy is an attractive therapeutic approach for treatment of GBM, for inducing (re)sensitization to cytotoxic or cytostatic drugs . It needs to be said that a full elucidation of the cause‐effect relationship between autophagy and cancer cells survival or death would be a very ambitious scope at this point.…”

Bioactive Phenolic Compounds in the Modulation of Central and Peripheral Nervous System Cancers: Facts and Misdeeds

“…Several studies demonstrate the efficacy of resveratrol in lowering tumorigenesis and preventing metastasis [23,89,90]. Resveratrol has a powerful capability of down-regulating the self-renewal and tumor-initiating capability of glioma stem cells obtained from GBM patients by inducing the p53/ p21 pathway [91].…”

Modulating autophagy as a therapeutic strategy for the treatment of paediatric high‐grade glioma

“…DNA-PK CS inhibition increased cell death in glioblastoma cells by the disruption of NHEJ and the sensitization of exposed cells to telomerase inhibitors (103). Strikingly, the inhibition of DNA-PK CS sensitized glioma cells to irradiation by inhibiting autophagy, supporting the theory of autophagy-mediated irradiation resistance and the dependence of HGG cells on autophagy (104,105).…”