Reactive oxygen species (ROS) function as critical signaling molecules in cancer biology, promoting proliferation, angiogenesis, and metastasis at controlled levels while inducing lethal damage when exceeding the cell’s buffering capacity. To survive under this state of chronic oxidative stress, cancer cells become dependent on a hyperactive antioxidant shield, primarily orchestrated by the Nrf2, glutathione (GSH), and thioredoxin (Trx) systems. These defenses maintain redox homeostasis and sustain oncogenic signaling, notably through the oxidative inactivation of tumor-suppressor phosphatases like PTEN, which drives the PI3K/AKT/mTOR pathway. Targeting this addiction to a rewired redox state has emerged as a compelling therapeutic strategy. Pro-oxidant therapies aim to overwhelm cellular defenses, with agents like high-dose vitamin C and arsenic trioxide (ATO) showing significant tumor-selective toxicity. Inhibiting the master regulator Nrf2 with compounds like Brusatol or ML385 dismantles the core antioxidant response. Disruption of the GSH system by inhibiting cysteine uptake with sulfasalazine or erastin potently induces ferroptosis, a non-apoptotic cell death driven by lipid peroxidation. Furthermore, the thioredoxin system is targeted by the repurposed drug auranofin, which irreversibly inhibits thioredoxin reductase (TrxR). Extensive preclinical data and ongoing clinical trials support the concept that this reliance on redox adaptation is a cancer-selective vulnerability. Pharmacologically tipping the redox balance beyond the threshold of tolerance offers a rational and powerful approach to eliminate malignant cells, defining a novel frontier for targeted cancer therapy.
Ranbhise et al. (2025) studied this question.