Double-edged role of antioxidants and oxidative stress: Focusing on cancer therapy and resistance

Oxidative stress and antioxidant systems are complex components of human physiology and pathology. Reactive oxygen species (ROS), previously viewed as undesirable byproducts of cellular metabolism, have now been identified as critical signaling agents that participate in cell proliferation, differentiation, and immune responses. Both endogenous and exogenous antioxidants play a critical role in redox homeostasis by countering surplus ROS and preventing oxidative injury. Nevertheless, growing evidence points to the paradoxical dual nature of antioxidants, casting doubt on their universally positive effects. This paradox is particularly pronounced in cancer. Although high levels of ROS promote tumor development and progression by causing genomic instability and activating oncogenic signaling, high levels of ROS can also cause cancer cell death and represent a major mechanism of action of anticancer therapies. Tumor cells respond by increasing their antioxidant capacity, which enables them to maintain ROS at levels that promote survival without causing cytotoxicity. Exogenous antioxidant supplementation can therefore disrupt this balance, potentially stimulating tumor growth, enabling metastasis, and diminishing the efficacy of ROS-dependent therapies like chemotherapy and radiotherapy. Moreover, plant-derived antioxidants, such as polyphenols and flavonoids, exhibit both antioxidant and pro-oxidant effects, highlighting the context-specificity of redox modulation in cancer. Although these compounds may have chemopreventive advantages, their impact on established malignancies is complex and requires additional research. This review provides a broad description of the duality of oxidative stress and antioxidants, specifically regarding their implications in cancer treatment and resistance. A better comprehension of redox biology is needed to develop more effective and personalized therapeutic interventions based on the specific regulation of oxidative stress.