The Fenton Reaction and Its Role in Cancer Development

by David W. Brown

The Fenton reaction is a fundamental chemical process that involves the catalytic decomposition of hydrogen peroxide (H₂O₂) by ferrous iron (Fe²⁺) to produce hydroxyl radicals (•OH). These hydroxyl radicals are among the most reactive oxygen species (ROS) and can cause extensive cellular damage by interacting with DNA, lipids, and proteins.

The Fenton reaction plays a crucial role in various physiological and pathological conditions, including neurodegenerative diseases, aging, and carcinogenesis. Recent studies have underscored the importance of the Fenton reaction in promoting cancer development by inducing oxidative stress, facilitating genomic instability, and modulating signaling pathways that favor tumor progression. 

The Fenton reaction was first described by Henry J. Fenton in 1894 and is characterized by the following reactions:

Primary Reaction: Fe²⁺ + H₂O₂ → Fe³⁺ + OH⁻ + •OH

Secondary Reactions: Fe³⁺ + H₂O₂ → Fe²⁺ + O₂H⁻ + H⁺
Fe²⁺ + O₂H⁻ → Fe³⁺ + O₂H•

These reactions lead to the production of hydroxyl radicals (•OH), which are highly reactive and capable of damaging biomolecules, ultimately contributing to various diseases, including cancer.

The involvement of the Fenton reaction in cancer is multifaceted, affecting multiple aspects of tumor biology. Below, I will explaine how this reaction contributes to carcinogenesis and tumor progression.

Oxidative stress is a hallmark of cancer and results from an imbalance between the production of ROS and the capacity of the cellular antioxidant defense system to neutralize them. The hydroxyl radicals generated from the Fenton reaction are particularly damaging to DNA, leading to mutations, strand breaks, and chromosomal instability.

Oxidative DNA damage often results in base modifications, such as 8-oxo-2′-deoxyguanosine (8-oxo-dG), which mispairs with adenine instead of cytosine during DNA replication, leading to mutagenesis. Mutations in key oncogenes and tumor suppressor genes, such as TP53, KRAS, and MYC, are frequently associated with oxidative damage and can drive cancer initiation and progression.

Lipid peroxidation, another consequence of hydroxyl radical activity, results in the oxidative degradation of lipids, particularly polyunsaturated fatty acids in cellular membranes. The breakdown of lipid membranes compromises cell integrity, promotes inflammation, and releases secondary reactive aldehydes such as malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE), which further contribute to mutagenesis and cell transformation.

Iron metabolism is intricately linked to cancer, as iron acts as a catalyst in the Fenton reaction. Cancer cells often exhibit dysregulated iron homeostasis, characterized by increased iron uptake and decreased iron efflux, which enhances ROS production. Several epidemiological studies have reported an association between high iron levels and an increased risk of various cancers, including liver, lung, and colorectal cancer.

Excess iron accumulation leads to chronic oxidative stress and DNA damage, thereby creating a microenvironment conducive to tumor development. Additionally, iron overload can induce ferroptosis, a form of regulated cell death dependent on iron and lipid peroxidation, which paradoxically may both suppress and promote tumor progression under different contexts.

Oxidative stress induced by the Fenton reaction activates multiple signaling pathways that support tumor growth and survival. Among the key pathways affected are:

  • Nuclear Factor-Kappa B (NF-κB): ROS activate NF-κB, a transcription factor that promotes cell proliferation, survival, and inflammation. NF-κB is constitutively activated in many cancers, driving tumor growth and resistance to apoptosis.
  • Mitogen-Activated Protein Kinases (MAPKs): ROS activate MAPK signaling, including ERK, JNK, and p38 pathways, which regulate cell proliferation, differentiation, and apoptosis.
  • Hypoxia-Inducible Factor 1-Alpha (HIF-1α): Iron dysregulation and oxidative stress stabilize HIF-1α, which promotes angiogenesis and metabolic adaptation in tumors, leading to increased survival under hypoxic conditions.
  • p53 Suppression: Persistent oxidative stress can inactivate the tumor suppressor p53, which normally induces cell cycle arrest and apoptosis in response to DNA damage.

The tumor microenvironment (TME) is highly influenced by oxidative stress, which alters the function of immune cells, stromal cells, and the extracellular matrix. The Fenton reaction contributes to the immunosuppressive nature of tumors by:

  • Inducing Macrophage Polarization: Oxidative stress skews macrophages toward the M2 phenotype, which promotes tumor growth and suppresses immune responses.
  • Enhancing Immune Checkpoint Expression: ROS can upregulate immune checkpoint molecules such as PD-L1, leading to immune evasion by cancer cells.
  • Modulating Fibroblast Activity: Cancer-associated fibroblasts (CAFs) respond to oxidative stress by secreting growth factors and extracellular matrix components that support tumor invasion and metastasis.

The Fenton reaction plays a pivotal role in cancer development by promoting oxidative stress, DNA damage, lipid peroxidation, and the activation of oncogenic signaling pathways. Iron overload exacerbates ROS generation, contributing to tumor progression and immune evasion.