Arsenic-modulated redox system and oxidative stress pathways

The arsenic-modulated redox system and oxidative stress pathways represent a complex biological network targeted by arsenic compounds, particularly arsenic trioxide (ATO), to induce cytotoxicity in malignant cells. Arsenic primarily acts by binding to thiol and selenothiol groups in key antioxidant enzymes, most notably thioredoxin reductase (TrxR), leading to its irreversible inhibition and the subsequent oxidation of the thioredoxin system [1.1.1]. This disruption, coupled with the depletion of cellular glutathione (GSH), results in a massive accumulation of reactive oxygen species (ROS) and the induction of the mitochondrial apoptotic pathway [1.1.3, 1.1.4]. In acute promyelocytic leukemia (APL), arsenic also directly targets the PML moiety of the PML-RARα fusion protein, triggering its sumoylation and proteasomal degradation, which restores normal myeloid differentiation [1.1.2]. While the system also activates the NRF2-mediated antioxidant response as a compensatory mechanism, the overwhelming oxidative stress eventually leads to cell death, making these pathways a critical focus for cancer therapeutics [1.1.1, 1.1.5]. The therapeutic window of arsenic is managed by its ability to selectively induce high levels of oxidative stress in cancer cells compared to normal cells [1.1.3].

Other names

Arsenic-induced oxidative stress responseThioredoxin-glutathione redox systemNrf2-Keap1 signaling pathwayArsenic-mediated apoptosis pathway

Inhibition of thioredoxin reductase; degradation of the PML-RARalpha fusion protein; depletion of cellular glutathione; induction of reactive oxygen species (ROS) and mitochondrial apoptosis.