Targeting autophagy for combating chemoresistance and radioresistance in glioblastoma

Abstract

Autophagy is an evolutionarily conserved catabolic process that plays an essential role in maintaining cellular homeostasis by degrading unneeded cell components. When exposed to hostile environments, such as hypoxia or nutrient starvation, cells hyperactivate autophagy in an effort to maintain their longevity. In densely packed solid tumors, such as glioblastoma, autophagy has been found to run rampant due to a lack of oxygen and nutrients. In recent years, targeting autophagy as a way to strengthen current glioblastoma treatment has shown promising results. However, that protective autophagy inhibition or autophagy overactivation is more beneficial, is still being debated. Protective autophagy inhibition would lower a cell's previously activated defense mechanism, thereby increasing its sensitivity to treatment. Autophagy overactivation would cause cell death through lysosomal overactivation, thus introducing another cell death pathway in addition to apoptosis. Both methods have been proven effective in the treatment of solid tumors. This systematic review article highlights scenarios where both autophagy inhibition and activation have proven effective in combating chemoresistance and radioresistance in glioblastoma, and how autophagy may be best utilized for glioblastoma therapy in clinical settings.

Keywords: Autophagy; Cell death; Chemoresistance; Glioblastoma; Radioresistance.

Fig. 1

Temozolomide (TMZ) and mechanism of action of TMZ for alkylation of DNA in glioblastoma cells. The chemical structure of TMZ contains an imidazole ring. It is a very small molecule (194 Da), which is promptly absorbed in the digestive tract. TMZ is a lipophilic compound and it is can go across the blood-brain barrier (BBB). In acidic pH of stomach, TMZ remains stable. But in slightly basic pH of blood and brain tissues, TMZ goes through spontaneous hydrolysis to produce the active metabolite 5-(3-methyltriazen-1-yl) imidazole-4- carboxamide (MTIC). Further, MTIC is hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC) and the highly reactive methyldiazonium cation. It is the methyldiazonium cation that alkylates the purine bases (guanine and adenine) in DNA in glioblastoma cells.

Fig. 2

The four distinct phases in mechanism of the autophagy and the corresponding molecular machinery. Purple circles represent the LC3 protein family, while red circles represent the Atg protein family. Orange ovals and the large red oval represent various intracellular structures that are degraded and recycled during autophagy. The mechanism of autophagy is explained in great detail in the text.

Fig. 3

Schematic presentation of the spectrum of autophagy inhibition vs. autophagy activation. Therapeutic strategies show how a push towards either direction can potentiate cell death. The middle of the figure demonstrates that all cells are undergoing a baseline level of autophagy in order to maintain homeostasis. The treatment modalities depicted represent cancer therapies and environmental conditions where autophagy inhibition or its activation has been demonstrated to promote cell death. For example, by inhibiting autophagy in hypoxic conditions, additional cell death will occur. By activating autophagy during radiation therapy or when chemoresistance is rampant, autophagic cell death can act as an additional cell death pathway.