Cellular stress responses as modulators of drug cytotoxicity in pharmacotherapy of glioblastoma

Despite the extensive efforts to find effective therapeutic strategies, glioblastoma (GBM) remains a therapeutic challenge with dismal prognosis of survival. Over the last decade the role of stress responses in GBM therapy has gained a great deal of attention, since depending on the duration and intensity of these cellular programs they can be cytoprotective or promote cancer cell death. As such, initiation of the UPR, autophagy or oxidative stress may either impede or facilitate drug-mediated cell killing. In this review, we summarize the mechanisms that regulate ER stress, autophagy, and oxidative stress during GBM development and progression to later discuss the involvement of these stress pathways in the response to different treatments. We also discuss how a precise understanding of the molecular mechanisms regulating stress responses evoked by different pharmacological agents could decisively contribute to the design of novel and more effective combinational treatments against brain malignancies.