Abstract
Glioblastoma multiforme is the most malignant and aggressive type of brain tumor, with a mean life expectancy of less than 15 months. This is due in part to the high resistance to apoptosis and moderate resistant to autophagic cell death in glioblastoma cells, and to the poor therapeutic response to conventional therapies. Autophagic cell death represents an alternative mechanism to overcome the resistance of glioblastoma to pro-apoptosis-related therapies. Nevertheless, apoptosis induction plays a major conceptual role in several experimental studies to develop novel therapies against brain tumors. In this review, we outline the different components of the apoptotic and autophagic pathways and explore the mechanisms of resistance to these cell death pathways in glioblastoma cells. Finally, we discuss drugs with clinical and preclinical use that interfere with the mechanisms of survival, proliferation, angiogenesis, migration, invasion, and cell death of malignant cells, favoring the induction of apoptosis and autophagy, or the inhibition of the latter leading to cell death, as well as their therapeutic potential in glioma, and examine new perspectives in this promising research field.
Highlights
Brain tumors are a group of highly aggressive and lethal neoplastic diseases [1]
Several studies have demonstrated that apoptosis and autophagy are upstream-regulated by common signaling pathways (RTKs/phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and p53)
It has been demonstrated that the (−)gossypol enantiomer (AT101) significantly increases cell death by mitochondrial dysfunction and autophagy induction in apoptosis-resistant human glioma cell lines; cell death was inhibited by a knockdown of pro-autophagic proteins like Beclin-1 and Atg5, and it was increased by a mTOR knockdown [308]
Summary
Brain tumors are a group of highly aggressive and lethal neoplastic diseases [1]. In recent years they reached an approximate incidence of 6–7 cases per 100,000 persons-year [2]. Grade IV astrocytomas, commonly called glioblastoma multiforme (GBM), are characterized by poorly differentiated neoplastic astrocytes with cellular polymorphism, nuclear atypia, high mitotic activity, necrosis, vascular proliferation, and thrombosis [5] These tumors exhibit a great local invasiveness, involving preferential anatomic pathways through the brain parenchyma, subarachnoid space, perivascular space, and white matter tracts; this suggests a variable permissiveness of stroma to the tumorigenic process. This involves the overactivation of the RAS/RAF, mitogen-activated protein kinase (MEK), extracellular-signal-regulated kinase (ERK), and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathways, by activating tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR), the platelet-derived growth factor receptor (PDGR), and the vascular endothelial growth factor receptor (VEGFR), which have been found upregulated in GBM [7,8,9] These signaling pathways are known to regulate cell proliferation, angiogenesis, migration, and invasion, as well as apoptosis and autophagy (Figure 1); a dysregulation of these signaling pathways favors tumor formation, progression, aggressiveness, and resistance to various therapies [10,11].
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