Drug Resistance in Glioblastoma: The Two Faces of Oxidative Stress

Abstract

Glioblastomas (GBM) are the most common primary brain tumor with a median survival of 15 months. A population of cells with stem cell properties (glioblastoma stem cells, GSCs) drives the initiation and progression of GBM and is localized in specialized microenvironments which support their behavior. GBM are characterized as extremely resistant to therapy, resulting in tumor recurrence. Reactive oxygen species (ROS) control the cellular stability by influencing different signaling pathways. Normally, redox systems prevent cell oxidative damage; however, in gliomagenesis, the cellular redox mechanisms are highly impaired. Herein we review the dual nature of the redox status in drug resistance. ROS generation in tumor cells affects the cell cycle and is involved in tumor progression and drug resistance in GBM. However, excess ROS production has been found to induce cell death programs such as apoptosis and autophagy. Since GBM cells have a high metabolic rate and produce high levels of ROS, metabolic adaptation in these cells plays an essential role in resistance to oxidative stress-induced cell death. Finally, the microenvironment with the stromal components participates in the enhancement of the oxidative stress to promote tumor progression and drug resistance.

Implications of Oxidative Stress in Glioblastoma Multiforme Following Treatment with Purine Derivatives

“…OS enhances the invasiveness of the cells, but the treatment with the compounds increases the redox modifications within the GBM spheroids, as revealed by the inhibition of the proliferation and differentiation, leading to the rupture of the outer layer of the cell spheroids. A hypothesis describing the effect of ROS in cancer cells suggests that, when these cells are subjected to external ROS-producing agents, the intracellular ROS levels increase more easily to reach a threshold and induce cell death [35]. Taken together, these findings indicate that 7-deazaKR demonstrates greater anticancer activity on cell spheroids than 8-azaKR.…”

“…ROS are produced in several metabolic processes and interfere with different intracellular targets such as lipids, proteins, and DNA, resulting in genomic instability and finally cell rupture [35,92]. KR treatment induced a significantly high level of oxidized lipids, which was correlated with the lowering of the 590/510 ratio of the fluorescence intensity (Figure 7E,F).…”

“…Cellular redox status is a balance of oxygen delivery, capacity, and consumption, and it prevents cell oxidative damage. ROS are produced constantly during cellular respiration and stimulate different signaling pathways in cancer cells [35]. GBM cells are known to have high metabolic rate and produce a high level of ROS, which promotes tumor progression and drug resistance.…”

“…Conducting therapies that affect the energy and redox balance in GBM cells is very challenging, with many limitations relying on the reduced susceptibility of cancer cells to medications [35]. It is established that nonmalignant cells maintain a moderate level of ROS, which contributes to the control of cell multiplication and differentiation.…”

“…GSH and other ROS scavengers exhibit a dual role in cancer cells, both maintaining a redox balance and promoting cancer progression and drug resistance in order to avoid cell death [99]. TMZ-resistant glioma cells have pronounced levels of glutathione reductase (GR) and GSH, and this is correlated with the regulation of redox status and drug response of GBM cells [35,88]. We also showed that, in response to KR and 7-deazaKR treatment, T98G cells show a rapid increase in total GSH content, which is likely a direct consequence of forcing the detoxification of elevated ROS (Figure 7G,H).…”