Autophagic and Apoptotic Pathways as Targets for Chemotherapy in Glioblastoma

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.

Salvianolate lyophilized injection induced autophagy against neuronal apoptosis through the Akt/mTOR pathway in Neuro-2a cells

“…The Akt/mTOR pathway maybe associated with both autophagy and apoptosis and possible common upstream pathway [58,59]. The inhibition of the PI3K/Akt/mTOR signal transduction pathway is consistently associated with triggering autophagy and reducing neuronal apoptosis [60].…”

Therapeutic Potential of Autophagy in Glioblastoma Treatment With Phosphoinositide 3-Kinase/Protein Kinase B/Mammalian Target of Rapamycin Signaling Pathway Inhibitors

“…The mTORC2 consists of mTOR, RPTOR-independent companion of mTOR complex 2 (RICTOR), MLST8, MAPK-associated protein 1 (MAPKAP1), DEPTOR, and protein observed with RICTOR (PROTOR) ( 22 ). The mTORC2 phosphorylates protein kinase C (PKC)δ, PKCζ, PCKγ, and PKCε, as well as AKT at Ser473 to regulate cell proliferation and cytoskeleton reorganization ( 10 , 22 ). Notably, the PI3K/AKT/mTOR is the only negatively regulated signaling pathway of PTEN.…”

“…Tyrosine kinase inhibitors (TKIs) specifically inhibit RTKs by binding the tyrosine kinase domain, which prevents RTK phosphorylation and activation of signaling cascades, such as the PI3K/AKT/mTOR pathway. Clinically, the most widely used anti-EGFR inhibitors to treat recurrent GB are gefitinib and erlotinib ( 10 ). However, the EGFR T790M mutation, acquired RTK MET gene amplification and PIK3CA mutations, share the same effect of reestablishing the downstream PI3K/AKT/mTOR pathway in the presence of the anti-EGFR inhibitors, ultimately converting a TKI-sensitive tumor into a TKI-resistant tumor ( 27 ).…”

“…Inhibition of mTOR induces autophagy by promoting the activation of several autophagy-related proteins involved in the initial stage of membrane isolation. Rapamycin, an early stage inhibitor of mTOR, binds the 12-kDa FK506-binding protein (FKBP12), which stabilizes the RPTOR–mTOR interaction and blocks the mTOR phosphorylation activity, ultimately leading to induction of autophagy ( 10 ). Rapamycin also mediates cell death after inhibition of mTOR in both GB cells with wild-type PTEN gene and GB cells without PTEN gene, indicating that a variety of signaling pathways are involved in autophagy regulation ( 14 ).…”

“…Therefore, inhibition of the PI3K/AKT/mTOR signaling pathway is an ideal strategy to improve the treatment of GB. Many studies have demonstrated that autophagy is critically involved in the treatment of GB with inhibitors of the PI3K/AKT/mTOR signaling pathway ( 8 – 10 ). Autophagy is an evolutionarily conserved and regulated complex process of degradation and recycling of cellular components participating in organelle turnover ( 11 ).…”