Role of Redox Status in Development of Glioblastoma

Abstract

Glioblastoma multiforme (GBM) is a highly aggressive neoplasia, prognosis remains dismal, and current therapy is mostly palliative. There are no known risk factors associated with gliomagenesis; however, it is well established that chronic inflammation in brain tissue induces oxidative stress in astrocytes and microglia. High quantities of reactive species of oxygen into the cells can react with several macromolecules, including chromosomal and mitochondrial DNA, leading to damage and malfunction of DNA repair enzymes. These changes bring genetic instability and abnormal metabolic processes, favoring oxidative environment and increase rate of cell proliferation. In GBM, a high metabolic rate and increased basal levels of reactive oxygen species play an important role as chemical mediators in the regulation of signal transduction, protecting malignant cells from apoptosis, thus creating an immunosuppressive environment. New redox therapeutics could reduce oxidative stress preventing cellular damage and high mutation rate accompanied by chromosomal instability, reducing the immunosuppressive environment. In addition, therapies directed to modulate redox rate reduce resistance and moderate the high rate of cell proliferation, favoring apoptosis of tumoral cells. This review describes the redox status in GBM, and how this imbalance could promote gliomagenesis through genomic and mitochondrial DNA damage, inducing the pro-oxidant and proinflammatory environment involved in tumor cell proliferation, resistance, and immune escape. In addition, some therapeutic agents that modulate redox status and might be advantageous in therapy against GBM are described.

Infiltrative and drug‐resistant slow‐cycling cells support metabolic heterogeneity in glioblastoma

“…Mitochondrial respiration functional assays with MitoTracker Orange, a dye that accumulates in active mitochondria where it gets oxidized, revealed significantly higher levels of reactive oxygen species (ROS) in SCCs than in FCCs (Figs I and EV3C). Of note, even though the majority of cellular ROS are normally produced by mitochondria, approximately a quarter can be produced from protein and lipid metabolism in the endoplasmic reticulum (ER) of glioma cells (Salazar‐Ramiro et al , ). Therefore, the differences in ROS levels observed from our MitoTracker Orange assays could have been due to either higher mitochondrial OxPhos activity or greater ER protein/lipid metabolism in SCCs than in FCCs.…”

Natural product HTP screening for attenuation of cytokine-induced neutrophil chemo attractants (CINCs) and NO2− in LPS/IFNγ activated glioma cells

“…CINCS are reportedly elevated as a consequence to ischemic (Wang et al, 2006) and vascular injuries (Weaver, Zhang, 2010), being coexpressed with GFAP, vimentin, synemin, nestin (Hol and Pekny, 2015) and alphaB-crystallin which is present in multiple sclerosis lesions (Liu et al, 2015). In the case of glioblastoma multiforme (GBM), excessive inflammation can drive not only a genetic instabilities, but also tumor proliferation, resistance and immunological evasion (Lin, Zhang, 2013, Polyzoidis, Koletsa, 2015, Salazar-Ramiro, Ramirez-Ortega, 2016). Much of this occurs due to glioma release of chemokines such as MCP1 can traffic monocyte infiltration and docking to glioma, then capable of transforming to an M2 pro-angiogenic phenotype which propels malignant aggressively (Leung, Wong, 1997, Liang, Bollen, 2008, Lindemann, Marschall, 2015).…”

“…(Li and Liu, 2015) Glial tumors originate from sites of chronic irritation/inflammation and once formed, perpetuate release of pro-tumor cytokines as means to drive tumor cell proliferation, resistance, and immune escape (Salazar-Ramiro et al, 2016). Glioma cells have enormous capacity to release chemokines such as MCP-1, which traffic recruitment of tumor associated monocytes (TAMS) (Leung et al, 1997) to infiltrate the glioma tumor bed (Lindemann et al, 2015, Polyzoidis et al, 2015).…”

Repair of DNA Double-Strand Breaks in Heterochromatin

“…These results need to be tempered by the fact that the formation of IRIF might be suppressed in HC, or that DSBs might be repaired with faster kinetics in cells with less heterochromatin, making the presence of IRIF an imperfect measure of the amount of damage. Additionally, the redox status can vary in different cell lineages, and thus cells with reduced ability to absorb reactive oxygen species may be more susceptible to DNA damage (e.g., [43,44]).…”