The concept of oxidative stress, well defined as a situation in which cells, tissues, or the whole body present an imbalance between reactive oxygen species (ROS) and antioxidant defenses in favor of ROS levels, is found in several acute and chronic diseases, including cancer. The equilibrium between ROS production and the ability of cells to avoid oxidative damage is a natural challenge for mammalian species since the energy production by oxidative pathways in mitochondria allows the continuous production of free radical and oxidative molecules. Pharmacological agents may generally use the modulation of oxidative balance to treat some diseases, or oxidative imbalance may represent a side effect of the drugs. Also, we need to keep in mind that oxidative stress caused by environmental (e.g., air pollution) and metabolic (e.g., obesity and diabetes) conditions is also associated with an increased risk of a variety of cancers.

Hyperproliferation of tumor cells is accompanied by high ROS production, but it is well known that cell stress response, antioxidant defenses, and resistance against the cytotoxic effects of chemotherapy is quite different in tumor compared to immune cells and other tissues. Thus, the tumor is able to adapt to conditions of oxidative burden while other cells may not present sufficient self-defense against oxidative damage. The mechanism of tumor self-protection involves increasing the levels of the major non-enzymatic antioxidant defense, glutathione (GSH). As a “hungry” cell, considering the common high-energy demand mainly by glucose uptake, tumors activate glucose-6-phosphate dehydrogenase (G6PD) and reroute glucose metabolism from glycolysis through the oxidative arm of the pentose phosphate pathway (PPP) toward nucleotide synthesis. In turn, the increase in nicotinamide adenine dinucleotide phosphate (NADPH) allows the increase in GSH and other antioxidant systems. Also, at a molecular level, the tumor evocates many transcription factors, including activator protein 1 (AP-1), heat shock factor 1 (HSF1), nuclear factor κB (NF-κB), nuclear factor-erythroid 2 p45-related factor 2 (NRF2), and tumor protein p53, representing a proliferative strategy accompanied by a robust cell stress defense.^,

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