Role of mitochondrial reactive oxygen species in glioblastoma drug resistance and strategies for therapeutic intervention

Glioblastoma (GBM) is the most aggressive tumor of CNS characterized by a poor prognosis mainly due to the resistance to the available treatments. Temozolomide (TMZ) is the gold standard for GBM treatment although this drug even in association with radiotherapy provides a median survival of 14.6 months. There are evidences that the increase in intracellular ROS is able to sustain gliomagenesis, tumor proliferation rate, and resistance to treatments by supporting proliferative pathways and metabolism as well as by generating genetic instability causing the establishment of protumorigenic mutants. At the same time, an increase in intracellular ROS, being involved in the oxidative damage of DNA, lipids, and proteins, is involved in the impairment of cell function, triggering also cell death. Reactive oxygen species (ROS) are highly reactive molecules originating from different enzymatic and nonenzymatic reactions occurring in mitochondria and other different intracellular organelles. They can have also an exogenous origin related to the effects of xenobiotics or radiations. Under basal conditions, ROS generation and their scavenging are tightly controlled, and redox homeostasis is maintained, but in case of an imbalance in ROS turnover, oxidative stress can occur producing cell damage. For these reasons, ROS modulation has been pursued by different treatment plans to increase cytotoxicity and overcome GBM resistance to treatment. Since the double-edged sword role covered by ROS, which mediates cell survival signaling, both a positive and a negative ROS modulation have been assessed for therapeutic purposes. In this chapter, the mechanisms involved in the relation between ROS and cell response to treatment are described with particular attention focused on the induction of chaperone-mediated autophagy (CMA) whose activity together with the reduction of hypoxia-inducible factor-1α (HIF-1) activity after treatment have been related to GBM cell responsiveness to TMZ.