Role of Oxidative Stress in Metabolic Reprogramming of Brain Cancer

Abstract

Brain cancer is known as one of the deadliest cancers globally. One of the causative factors is the imbalance between oxidative and antioxidant activities in the body, which is referred to as oxidative stress (OS). As part of regular metabolism, oxygen is reduced by electrons, resulting in the creation of numerous reactive oxygen species (ROS). Inflammation is intricately associated with the generation of OS, leading to the increased production and accumulation of reactive oxygen and nitrogen species (RONS). Glioma stands out as one of the most common malignant tumors affecting the central nervous system (CNS), characterized by changes in the redox balance. Brain cancer cells exhibit inherent resistance to most conventional treatments, primarily due to the distinctive tumor microenvironment. Oxidative stress (OS) plays a crucial role in the development of various brain-related malignancies, such as glioblastoma multiforme (GBM) and medulloblastoma, where OS significantly disrupts the normal homeostasis of the brain. In this review, we provide in-depth descriptions of prospective targets and therapeutics, along with an assessment of OS and its impact on brain cancer metabolism. We also discuss targeted therapies.

Keywords: RNS; RONS; ROS; brain cancer; oxidative stress; tumor microenvironment.

Figure 1

Role of ROS and RNS in genetic damage and BBB damage, causing oxidative stress and cancer in the brain. NOXs in reaction with O₂⁻ produce ROS and RNS, in turn activating MMPs (matrix metalloproteinases), which damage the blood–brain barrier (BBB) and cause oxidative stress in the brain. ROS activate VEGFA and TGFβ, which leads in the formation of ROS and RNS. The antioxidant SOD2 catalyzes H₂O₂, which activates ROS AND RNS and also leads to genetic damage and a loss of the tumor suppressor (p53) and cell cycle regulators (CDK4,6), which leads to cancer activation. Smad7 and TIMP1 act as the inhibitors of ROS AND RNS activity. Abbreviation: ROS—reactive oxygen species; RNS—reactive nitrogen species; BBB—blood–brain barrier; ETC—electron transport chain; MMP—matrix metalloproteinase; SOD2—superoxide dismutase-2; VEGFA—vascular endothelial growth factor A; TGFβ—transforming growth factor-beta; Smad7—suppressor of mothers against decapentaplegic-7; TIMP1—tissue inhibitor of metalloproteinase.

Figure 2

Metabolic programming in glioblastoma cells. Glycolysis and glutaminolysis accelerate the TCA cycle in mitochondria and the IDH catalyze the oxidative decarboxylation of isocitrate to create CO₂ and αKG.