Antioxidant Enzymes and Their Potential Use in Breast Cancer Treatment

Abstract

According to the World Health Organization (WHO), breast cancer (BC) is the deadliest and the most common type of cancer worldwide in women. Several factors associated with BC exert their effects by modulating the state of stress. They can induce genetic mutations or alterations in cell growth, encouraging neoplastic development and the production of reactive oxygen species (ROS). ROS are able to activate many signal transduction pathways, producing an inflammatory environment that leads to the suppression of programmed cell death and the promotion of tumor proliferation, angiogenesis, and metastasis; these effects promote the development and progression of malignant neoplasms. However, cells have both non-enzymatic and enzymatic antioxidant systems that protect them by neutralizing the harmful effects of ROS. In this sense, antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), thioredoxin reductase (TrxR), and peroxiredoxin (Prx) protect the body from diseases caused by oxidative damage. In this review, we will discuss mechanisms through which some enzymatic antioxidants inhibit or promote carcinogenesis, as well as the new therapeutic proposals developed to complement traditional treatments.

Keywords: antioxidant; breast cancer; catalase; glutathione peroxidase; glutathione reductase; peroxiredoxin; superoxide dismutase; thioredoxin reductase.

Figure 1

The antioxidant enzymatic system is made up of six enzymes: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), thioredoxin reductase (TrxR), and peroxiredoxin (Prx). SOD eliminates the 2 O₂^·−, generating two H₂O₂ molecules and CAT destroys them, producing H₂O and O₂. GPx, GR, TrxR, and Prx remove H₂O₂ by regulating the redox conditions of glutathione, thioredoxin, and NADPH.

Figure 2

Relationship between antioxidant enzymes and ferroptosis. GPx4, Prx6, and GR act as negative regulators of iron-mediated death. GPx4 and Prx6 use GSH as a reducer and by inhibiting them it is possible to activate ferroptosis. Similarly, the concentration of these selenoproteins can be reduced by inhibition of selenophosphate synthetase 2 (SEPHS2), which is necessary for cancer cells to detoxify the selenide that enters through SLC7A11 and is useful in its biosynthesis. Furthermore, the GSH content can also decrease due to the activation of SOD and the modulation of the cystine-glutamate antiporter (SLC7A11) by TrdxDC12. Also, the inhibition of CAT causes the accumulation of Fe²⁺, favoring the Fenton reaction and, in turn, ferroptosis.

Figure 3

Characteristics of some nanoparticles used in nanomedicine in the treatment of BC.