Amino Acids and Cancer Treatment: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Lyudmila Bel'skaya.

The antioxidant properties of amino acids and their role in the physicochemical processes accompanying oxidative stress in cancer remain unclear. Cancer cells are known to extensively uptake amino acids, which are used as an energy source, antioxidant precursors that reduce oxidative stress in cancer, and as regulators of inhibiting or inducing tumor cell-associated gene expression. This revNiew examines nine ne amino acids (Cys, His, Phe, Met, Trp, Tyr, Pro, Arg, Lys) are examined, which play a key role in the non-enzymatic oxidative process in various cancers. Conventionally, these amino acids can be divided into two groups, in one of which the activity increases (Cys, Phe, Met, Pro, Arg, Lys) in cancer, and in the other, it decreases (His, Trp, Tyr). 

  • amino acids
  • cancer
  • oxidative stress
  • non-enzymatic antioxidant system

1. Introduction

Recent research in the field of cancer cell metabolism is significantly changing our understanding of metabolic processes such as the redox mechanism, carbon metabolism, epigenetic regulation, and immune response associated with tumorigenesis and metastasis [1,2][1][2]. This includes reconsidering the role of amino acids and changes in their composition during oncological processes. It is known that cancer cells intensively absorb amino acids and use them as a source of energy, precursors of antioxidants that reduce the level of oxidative stress in cancer, and also as regulators of inhibition or induction of gene expression associated with the regulation of tumor cell activity [3].
The pathophysiological process begins with a change in the oxidative capacity of proteins, through modification of the structure and activity of protein binding sites with other molecules, which are elements in the cascade reaction of antioxidant activity [4,5,6][4][5][6]. The choice of the oxidative process path and its activity is determined the features of the reactive type like its the activity and specificity. It is deteremined by the cell type, state of cell differentiation, state of the extracellular environment, level of antioxidants and antioxidant enzymes. The activity of the redox process will depend on the specific type of modified protein, and this, in turn, depends on the amino acid composition of the protein. In addition to the above, there is the concept of protein network formation, which explains the coordinated interaction between proteins and the activation of the redox pathway [7,8][7][8].
A number of studies on model systems have established that amino acids exhibit the ability to reduce damaging oxidative effects of various natures at different levels of biological organization [9]. These effects probably happen because of the physicochemical properties of individual amino acids, which are connected to their ability to react with reactive oxygen species. For example, the ability of citrulline and Arg to eliminate the superoxide anion radical has been shown, and leads to normalization of the functioning of the heart muscle when exposed to oxidizing factors [10,11][10][11]. It has been established that proline is an effective scavenger of singlet oxygen and prevents cell death under oxidative stress [12]. The ability of His to intercept peroxyl radicals and prevent the carboxylation of proteins and the formation of protein cross-links has been revealed [13]. It was discovered that a number of amino acids prevent the formation of 8-oxoguanine in DNA by protecting guanine from one-electron oxidation to the guanine radical cation [14]. It is still unclear to what extent the change in amino acid composition is tissue-specific, as well as how certain types of cancer are metabolically dependent on a specific amino acid composition [15].

2. Amino Acids as Therapeutic Targets for Cancer Treatment

Scientists around the world are actively exploring the possibility of regulating amino acid metabolism in oncology [158][16]. In many cases, therapeutic targeting of tumor cell metabolism produces better results with fewer side effects [121][17]. For example, therapies targeting the regulation of essential amino acids, such as Met, have beneficial effects. This was demonstrated by scientists using dietary Met restriction in mice and rats, which resulted in an increase in the lifespan of mice and rats [159][18]. It has long been noted that limiting the supply of amino acids leads to a slowdown in tumor growth [159,160][18][19]. Thus, the enzyme arginase is attracting increasing interest as a therapeutic target. There are two types of isoforms of this enzyme, arginase 1 (ARG1) and arginase 2 (ARG2) [161][20]. Abnormal expression of these enzyme isoforms has been reported to frequently occur in cancers such as breast, gastric, colorectal, and liver cancer [162,163,164,165,166][21][22][23][24][25]. In addition, signaling pathways associated with arginase, such as arginase/PI3K/RAC-alpha serine/threonine-protein kinase (AKT)/mTOR, arginase/signal transducer and activator of transcription 3 (STAT3), and arginase/mitogen-activated protein kinase (MAPK), can be influenced [167][26]. For Lys, the enzyme lysine-specific histone demethylase 1A (KDM1A/LSD1) was discovered. It shows activity in relation to the development, metastasis, progression, and therapy resistance of cancer [168][27]. Pharmacological modification of Cys residues affects the biological activity of this molecule, thereby demonstrating a therapeutic effect [169][28]. Thus, it is possible to regulate the entry of cysteine into the cell by blocking the xCT/SLC7A11 transporter [100][29]. SLC7A11 has been found to be widely expressed in a variety of cancers, and has poor survival rates in patients with breast cancer, prostate cancer, and papillary thyroid carcinoma [170][30]. In prostate cancer patients, a positive association between xCT expression with invasion and metastasis has been widely found, through an influence on the redox status of the tumor microenvironment [171][31]. It is also possible to influence GSH peroxidase 4 (GPX4), triggering the mechanism of ferroptosis [172,173,174,175,176,177][32][33][34][35][36][37]. A positive effect in cancer therapy was discovered by suppressing the entry of hydrogen sulfide into cancer cells, which, through activation of GLUT, enhances the uptake of glucose and its glycolysis with the subsequent production of ATP, which is spent on maintaining the life of the cancer cell [178][38]. Hydrogen sulfide is produced by three enzymes, namely cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfatansferase (3MST). CBS knockdown reduced oxygen consumption and ATP production in colon and ovarian cancer cells [179,180][39][40]. Suppression of CSE expression in endothelial cells reduced their ability to induce angiogenesis in breast cancer cells [181][41]. Cys may also have an antitumor effect through its byproduct, taurine. Cysteine dioxygenases catalyze the oxidation of Cys to cysteine sulfinate. Cysteine sulfinic acid decarboxylase catalyzes the reaction, and carboxyl groups are removed to form hypotaurine, which subsequently generates taurine [182][42]. Taurine has been shown to have cytoprotective functions and maintain cell homeostasis [183][43]. Increased taurine content has shown an inhibitory effect on the growth of colon cancer [184][44], lung cancer [185][45], HCC [186][46], melanoma [187][47], and breast cancer [188][48]. There are a number of other possibilities for influencing Cys, providing an antitumor effect, for example, through protein kinases and phosphatases [189,190,191,192][49][50][51][52]. An antitumor effect was demonstrated when His was added to HCC tumor cells. It considerably reduces the release of cytokines in response to liver injury [193][53]. There is a decrease in the expression of tumor markers that are associated with glycolysis (GLUT1 and HK2), inflammation (pSTAT3), angiogenesis (VEGFB and VEGFC), stem cells (CD133), metastasis (snail/slug), and cell migration [194][54]. Pro synthesized by proline synthase PYCR1 through cGMP-PKG enhances the hallmarks of stem cell carcinoma. Knockdown of proline synthetase PYCR1 showed a significant reduction in breast cancer growth [195][55]. Another therapeutic target is the enzyme proline dehydrogenase (PRODH) [196][56]. On the one hand, increased expression of PRODH induces apoptosis [197,198][57][58] of breast cancer cells. On the other hand, it stimulates metastasis to the lung. Although there is currently no clear conclusion on the stimulation and inhibition of this enzyme, since its role in cancer metabolism is twofold, further study of the possibility of using proline dehydrogenase as a therapeutic target is very important [199][59]. Inhibition of Pro synthesis itself may also reduce the synthesis of collagen, which is essential for the growth and development of cancer cells, and the extracellular matrix [200][60]. It is necessary to find a balance between reducing and completely suppressing the synthesis of extracellular matrix components, since its complete ablation can free tumor cells from the limiting barrier [201,202,203][61][62][63]. To limit the availability of Trp and prevent its use along the kynurene pathway, it is possible to influence the direct transport of tryptophan into the cancer cell, suppress the activity of Trp 2,3-dioxygenase (TDO2) and indoleamine 2,3-dioxygenase 1 (IDO1), and inhibit N′-formylkynurenine formamidase (FAMID), Kyn aminotransferase 1 (KAT1) and kynureninase (KYNU), nicotinamide phosphoribosyltransferase (NMPRT), nicotinamide mononucleotide adenylyltransferase (NMNAT) aryl hydrocarbon receptor (AhR), interleukin 4-induced protein 1 (IL-4I1), poly (ADP-ribose) polymerase (PARPs), and protein acetylaters (SIRTs). All this is a potential target for depriving the cancer cell of its ability to maintain its vital activity [204][64]. Tyrosine kinase inhibitors have become very widely used in the treatment of various types of cancer. Medicines containing this enzyme, in addition to having a positive effect in the treatment of oncology, also have a number of serious side effects. This forces scientists and physicians to look for new ways to use this approach [205][65]. Phe has not yet been presented as a therapeutic target for the supervision of cancer patients. This area requires additional study and understanding of possible control points in the life of a cancer cell.

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