Written by | qiReactive oxygen species (ROS) have been implicated in the pathogenesis of a variety of diseases, most well-known for the destruction of macromolecules by ROS, while in some cases, it can act as a second messenger to regulate various cascades. Antioxidants can alleviate or eliminate oxidative damage to specific target molecules by reacting with ROS, cancer cells typically produce higher levels of ROS and theoretically need more antioxidants to act as buffers, but the current findings seem to contradict this view, and the role of antioxidants in cancer remains controversial. Recently, from the University of Rochester Medical Center in the United Statesisaac spencer harrisWaitmolecular cellAn article was published in the magazine entitledregulation of antioxidants in cancerThe opinion article is hereThe current research progress related to antioxidants in cancer is discussed
Large clinical trials 20 years ago not only failed to prove the clinical benefits of antioxidants for cancer, but instead confirmed that they lead to an increase in all-cause mortality。Studies have shown that certain antioxidants act as "pro-oxidants" (i.e., vitamin C) at higher levelsand whether antioxidants have systemic harmful effects in humans other than cancer remains to be revealed. In addition, oxidative damage is an important component of the cytotoxicity of several anticancer drugs (e.g., radiotherapy), so the use of antioxidants may reduce the efficacy, which in turn leads to higher rates and mortality. In addition to dietary antioxidants, endogenously produced antioxidants play a key role in cancer cell biology. For example, nuclear factor-erythrocyte 2-related factor 2 (NRF2) is a major transcriptional regulator of several antioxidant enzymes and has also been shown to support tumorigenesis, and cancers with elevated NRF2 levels are associated with poor prognosis. However, some studies have shown that NRF2 can act as a tumor suppressor and slow down cancer progression, suggesting that the role of antioxidants in carcinogenesis is complex and dynamic. 
Figure 1Dynamic regulation of antioxidants in cancer. Interestingly, studies have shown that metastatic cancer cells have higher levels of oxidative stress compared to primary cancers, and conversely, an increase in oxidative stress in muscle tissue prevents metastasis, illustrating that topical antioxidants and ROS significantly affect the metastatic potential of some cancers. In addition, age also appears to affect the role of antioxidants in cancer, with studies showing that several mouse models of antioxidant depletion have shown increased cancer rates later in life. The availability of amino acids, oxygen content, and other local characteristics in the tumor microenvironment (TME) determine the suitability for cancer growth. In pancreatic tumors, tumor interstitial fluid (TIF) is low in antioxidant precursor substances (cystine), while antioxidant glutathione (GSH) precursors such as glycine are abundant in some malignancies and TME. Little is known about the subcellular compartmentalization of ROS and antioxidants. Until recently, it was discovered that mitochondria were fed into GSH via SLC25A39 to maintain iron-sulfur clusters in the electron transport chain, and through cysteine analysis and functional genomic screening, it was found that the accumulation of ROS in the nucleus can initiate a signaling cascade that inhibits ROS production in mitochondria, although mitochondria are generally considered to be the core site of ROS production. In addition, a high degree of redox reaction also occurs in the endoplasmic reticulum (ER), and the GSH-independent antioxidant enzyme peroxidase (PRDX4) is also involved in maintaining ER redox homeostasis in tumor cells, suggesting that the endoplasmic reticulum can serve as a unique site for redox buffering in cells. In addition to some of the above, there are many questions, such as whether there are differences in antioxidant dependence between tumors derived from different tissues and organsHow does persulfide of antioxidant molecules affect tumor growth?How does the role of cysteine in redox buffering balance the need for cysteine with other key tumor processes (e.g., protein translation, CoQA synthesis).How is selenocysteine, a key amino acid of antioxidant enzymes, distributed in antioxidant proteins (e.g., TXNRD1 2, GPX4) in cancer cellsAnd what other molecules have yet to be discovered as "new" antioxidants?Because standard chemoradiotherapy is associated with the depletion of antioxidants and the induction of oxidative stress, poor knowledge of antioxidants can lead to unsatisfactory and even dangerous clinical outcomes. If the regulatory role of antioxidants in cancer can be elucidated, more and more reliable strategies will be provided for cancer patients. Original link:Plate maker: Eleven.
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