Antioxidants: Positive or Negative Actors?

Abstract

The term "antioxidant" is one of the most confusing definitions in biological/medical sciences. In chemistry, "antioxidant" is simply conceived "a compound that removes reactive species, mainly those oxygen-derived", while in a cell context, the conceptual definition of an antioxidant is poorly understood. Indeed, non-clinically recommended antioxidants are often consumed in large amounts by the global population, based on the belief that cancer, inflammation and degenerative diseases are triggered by high oxygen levels (or reactive oxygen species) and that through blocking reactive species production, organic unbalances/disorders can be prevented and/or even treated. The popularity of these chemicals arises in part from the widespread public mistrust of allopathic medicine. In fact, reactive oxygen species play a dual role in dealing with different disorders, since they may contribute to disease onset and/or progression but may also play a key role in disease prevention. Further, the ability of the most commonly used supplements, such as vitamins C, E, selenium, and herbal supplements to decrease pathologic reactive oxygen species is not clearly established. Hence, the present review aims to provide a nuanced understanding of where current knowledge is and where it should go.

Keywords: antioxidants; cancer; inflammation; natural products; reactive species.

Figure 1

Overview of reactive oxygen signaling. Superoxide, which can arise from NADPH oxidases action or mitochondrial leak, oxidatively inactivate p53, PTEN, and IkB, leading to Akt and NF-κB activation. Reactive oxygen inhibition with NADPH oxidase inhibitors can reverse this phenotype. Glutathione formation through Nrf2 activation can lead to reactive oxygen reduction and, thus, possibly an NF-κB decrease but also may react with chemotherapy and radiation generated species, thus, protecting tumor cells.

Figure 2

Potential outcomes of antioxidants at differing tumorigenesis stages. The presence of a driver mutation in a primary cell leads to reactive oxygen-mediated endoplasmic reticulum (ER) stress. Normally, this could lead to senescence, in which P16ink4a and FOXO4 senescence markers are elevated, as well as NF-κB activation. This leads to a persistent senescent phenotype which cannot re-enter the cell cycle. On the other hand, ER stress relief with an antioxidant, or tumor suppressor (i.e., p16ink4a) loss leads to clonal cells expansion with driver mutations. This may lead to carcinogenesis. In advanced tumors, NF-κB might be activated by ROS and a ROS blockade may lead to NF-κB activation decrease and chemotherapy and radiation sensitivities increase.