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Interplay of oxidative stress and antioxidant mechanisms in cancer development and progression.

  • 2025-09-04
  • Archives of toxicology 100(1)
    • Klaudia Jomova
    • Suliman Y Alomar
    • Richard Valko
    • Lukas Fresser
    • Eugenie Nepovimova
    • Kamil Kuca
    • Marian Valko

Study Design

Type
Review
Cellular systems responsible for the formation and removal of reactive oxygen species (ROS), functioning within physiological limits, are essential for maintaining intracellular redox balance. This state is known as oxidative eustress. Key redox signaling molecules, such as superoxide anion radical (O2•-) and hydrogen peroxide (H2O2), operate at nanomolar concentrations and are produced by NADPH oxidases (regulated by various factors), the mitochondrial electron transport chain (ETC), and numerous enzymes. In addition, cell signaling is influenced by nitric oxide (NO•) and reactive lipid species. Disruption of ROS signaling can lead to oxidative stress, a harmful condition associated with many chronic diseases, including cancer. The dual nature of ROS is evident in premalignant and malignant cells at all stages of tumor development, including proliferation, migration/invasion, angiogenesis, inflammation, immune evasion, and metastasis. ROS can promote tumor formation by regulating immune cells, mitochondrial metabolism, DNA methylation, DNA damage [such as the DNA oxidation product, 8-oxo-dG, resulting from hydroxyl radical (•OH) attack], and other mechanisms. The tumor-promoting activity mediated by H2O2 manifests through the promotion of epithelial-to-mesenchymal transition (EMT) and the formation of the tumor microenvironment (TME) by tumor-associated macrophages. While ROS are vital for tumor initiation and growth, their excessive production can also have anticancer effects by inducing senescence, apoptosis, or necrosis. ROS-related anticancer mechanisms include mitochondrial dysfunction, p53-dependent apoptosis, iron-dependent ferroptosis, activation of endoplasmic reticulum stress, inhibition of growth signaling pathways (such as the epidermal growth factor pathway, EGF), among others. Tumor cells employ a range of adaptive mechanisms to effectively maintain ROS levels within a dynamic range that promotes proliferation while preventing cell death. This regulation is achieved by fine-tuning the effects of antioxidants throughout all stages of cancer. During early tumor development, characterized by increased oncogene-induced oxidative stress, cancer cells depend on glutathione (GSH) and upregulated antioxidant gene expression controlled by nuclear factor erythroid 2-related factor 2 (NRF2) to maintain redox balance. The opposing roles of certain antioxidant enzymes, such as Mn-SOD (SOD2), illustrate the same duality as ROS, acting as potential tumor suppressors during early carcinogenesis and as tumor promoters during metastasis. Low-molecular-weight antioxidants such as vitamins C (ascorbate) and E (tocopherols), carotenoids (e.g., lycopene, β-carotene), flavonoids (e.g., quercetin), and isoflavones demonstrate effective antioxidant activity in vitro, but their anticancer effects in clinical settings remain unproven. Understanding the influence of the antioxidant network and the redox threshold on epithelial-to-mesenchymal transition and key tumor microenvironment components could lead to more effective therapeutic strategies. This review explores the dual roles of ROS and antioxidants throughout different stages of cancer progression.

Research Insights

  • Blood Orange→Reduced Cancer Incidence

    Low-molecular-weight antioxidants such as vitamins C (ascorbate) and E (tocopherols), carotenoids (e.g., lycopene, β-carotene), flavonoids (e.g., quercetin), and isoflavones demonstrate effective antioxidant activity in vitro, but their anticancer effects in clinical settings remain unproven.

    Effect
    Neutral
    Effect size
    Small
  • Quercetin→Reduced Cancer Incidence

    Low-molecular-weight antioxidants such as vitamins C (ascorbate) and E (tocopherols), carotenoids (e.g., lycopene, β-carotene), flavonoids (e.g., quercetin), and isoflavones demonstrate effective antioxidant activity in vitro, but their anticancer effects in clinical settings remain unproven.

    Effect
    Neutral
    Effect size
    Small
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