Oxidative Stress and Redox Targeting in Cancer Cells1,2
All human cells carry out their regular functions by a series of metabolic processes that generate reactive oxygen species (ROS) as a byproduct.1 When ROS are in excess, they can cause damage to DNA, eventually leading to cell death.1,3 Under physiologic conditions, all human cells maintain a redox balance between the generation of ROS and protective antioxidant systems that remove ROS.1
Cancer cells, including cancer stem cells (CSCs), generate higher levels of ROS than normal cells, partially due to a higher rate of cellular metabolism.1 Therefore, they also express higher levels of intracellular antioxidants, particularly NQO1, compared to cells in normal tissue.1,2 The resulting redox balance determines the specific "redox signature" of each cell, which can have downstream effects on oncogenic signaling pathways, including STAT3.
Research suggests that a subset of cancer cells, including some CSCs, possess a distinct redox signature that may make them susceptible to approaches that generate cytotoxic levels of ROS. These cells signal to other cells in the tumor microenvironment and promote the phosphorylation of STAT3. The presence of phosphorylated STAT3 in a tumor may indicate this redox signature and favorability to ROS-generating intervention.
The cytotoxic disruption of redox homeostasis may potentially be exploited therapeutically as a mechanism of action against cancer cells.1
NQO1=NAD(P)H:quinone dehydrogenase 1.
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- Lee HY, Parkinson EI, Granchi C, et al. Reactive oxygen species synergize to potently and selectively induce cancer cell death. ACS Chem Biol. 2017;12(5):1416-1424.
- Davalli P, Marverti G, Lauriola A, D'Arca D. Targeting oxidatively induced DNA damage response in cancer: opportunities for novel cancer therapies. Oxid Med Cell Longev. 2018;2018:2389523. doi:10.1155/2018/2389523.
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- Chang A-Y, Hsu E, Patel J, et al. Evaluation of tumor cell–tumor microenvironment component interactions as potential predictors of patient response to napabucasin [manuscript under review]. Mol Cancer Res. 2019.
- Liu J, Wang Z. Increased oxidative stress as a selective anticancer therapy. Oxid Med Cell Longev. 2015;2015:294303. doi:10.1155/2015/294303.
- Sokolenko AP, Imyanitov EN. Molecular diagnostics in clinical oncology. Front Mol Sci. 2018;5:76. doi:10.3389/fmolb.2018.00076.