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Subjects:
Biochemistry & Molecular Biology
Green tea’s (Camellia sinensis) anticancer and anti-inflammatory effects are well-known. Catechins are the most effective antioxidants among the physiologically active compounds found in Camellia sinesis. Catechins have the ability to effectively neutralize reactive oxygen species. The catechin derivatives of green tea include epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG) and epigallocatechin gallate (EGCG). EGCG has the greatest anti-inflammatory and anticancer potential. Notably, catechins in green tea have been explored for their ability to prevent a variety of cancers.
- green tea catechins
- EGCG
- anticancer
- cancer prevention
- cancer therapy
1. Introduction
Camellia sinensis, more often known as tea, is one of the world’s oldest and most consumed beverages. The primary factors that determine the classification of green tea are the history of the production of green tea leaf processing, the location of its origin, and the type of soil on which the tea bushes have grown. The most important producers of green tea are China, Taiwan and Japan. The methodology that is used to produce green tea and black tea is the primary factor that differentiates the two types of tea [1,2,3,4]. There are numerous varieties of green tea, each of which is distinguished from others by the flavor it imparts and the antioxidant capacity it possesses. The methodology involved in tea extraction has a significant weightage on the amount of antioxidant potential that green tea possesses. When compared to black tea, the amount of catechins found in green tea is significantly higher. During the fermentation process, catechins can oxidize into theaflavins, which leads to the occurrence of this effect. In addition, it is essential to be aware of the fact that the concentration of catechins in tea directly correlates to the level of antioxidant activity it possesses. The amount of polyphenolic chemicals, such as catechins, that are produced by Camellia sinensis is directly proportional to the environmental and agricultural circumstances under which it is grown. It is important to note that the antioxidant activity of a green tea infusion rises along with the temperature [5,6], which is an interesting phenomenon. The proportion of green tea’s total content changes based on a range of environmental factors, such as the growing circumstances, the soil, the climate, and other external factors such as light, geography, microorganisms, and temperature [7]. Included in the catechins (flavan-3-ol) family of flavonoids that are found in tea are the following compounds: (−)-epigallocatechin gallate (EGCG), (−)-epicatechin gallate (ECG), (−)-epigallocatechin (EGC), and (−)-epicatechin (EC). One of the most widespread and structurally varied classes of polyphenols is called flavonoids. Strong antioxidant activities are possessed by the molecules as a result of the presence of a large number of hydroxyl groups [1,2]. There are more than 10 different families of chemicals that are found in green tea’s chemical composition. The primary components include catechins, phenolic acids, polyphenolic compounds, amino acids, proteins, and lipids [8,9,10,11,12,13]. Green tea that has not been fermented is notable for being the best source of catechins. The antioxidant capabilities of green tea leaves can vary widely, depending on factors such as their variety and place of origin [13,14,15,16]. Catechins are found naturally in a variety of foods and beverages, including black tea, coffee, berries, grapes, and wine. It is recommended to incorporate foodstuff specifically containing catechins in one’s diet on a daily basis [17] because of the multiple qualities of catechins that are beneficial to one’s health. The catechin group is believed to have the most important impact due to its chemopreventive, anti-inflammatory, and antioxidant properties [13,14,15,16,17,18]. Catechins have the antioxidant properties of scavenging reactive oxygen species, decreasing the generation of free radicals, and preventing lipid peroxidation. These are the fundamental roles that catechins play in plants. According to the research that has been published so far, the antioxidant activity of catechins found in green tea and their significant impact on the prevention of diseases associated with modern civilization are largely determined by the presence of structural groups in the molecules, in addition to the number of hydroxyl groups [3,4,19,20]. Evidence suggests that green tea may help reduce the risk of numerous types of cancer, including those of the esophagus, lung, prostate, stomach, breast, pancreas, intestinal tract, and bladder [14,15,16,17].
2. Chemical Composition of Green Tea Catechins
Green tea has a protein content of about 15–20%, which includes amino acids such as L-theanine [10], tryptophan, tyrosine, leucine, threonine, 5-N-ethylglutamine, lysine, glutamic acid, serine, glycine, valine, aspartic acid, and arginine. The protein content of green tea can be broken down into two categories: complete proteins and incomplete proteins. Green tea may also contain trace elements, including magnesium, chromium, manganese, calcium, copper, zinc, iron, selenium, salt, cobalt, or nickel, as well as carbohydrates, including glucose, cellulose, and sucrose [9,10,11,12,13,14,15,16,17,18,21,22]. In addition, green tea is abundant in sterols and lipids, including linoleic and linolenic acid, as well as some vitamins (A, B, C, and E); the highest concentrations of these nutrients can be found in Gyokuro tea (approximately 10 mg) and Sencha tea (4 mg). Vitamin K is present in only trace amounts. Matcha tea is the sole known source of vitamin A. Phosphorus, fluorine, and iodine are some of the macro-elements that can be obtained from drinking green tea. Additionally, green tea is an excellent source of phosphorus. Another characteristic of green tea is the presence of the diphenylpropanoid skeleton, which has the chemical formula C6C3C6 [10,11,12]. In addition, green tea has a high concentration of xanthine bases, such as theophylline and caffeine [21], as well as a variety of pigments, including chlorophyll and carotenoids. It is important to note that the chemical makeup of green tea also consists of phenolic acids, which can include gallic acid, as well as volatile chemicals, which can include alcohols, esters, hydrocarbons, and aldehydes. Phenolic acids, which include proanthocyanidins and also gallic acid esters with monosaccharides, have a significant influence on the characteristics of green tea infusion. These phenolic acids also play a role in the formation of catechins. The collection of chemicals known as polyphenols also includes flavonoids, flavandiols, and flavols, in addition to the phenolic acids that were just discussed. According to the data that are now available, these chemicals may account for as much as 30–35% of green tea’s dry matter. Catechins are the most common type of flavonoids found in green tea. When compared to black or Oolong tea, the amount of catechins found in green tea is significantly higher. As mentioned above, the catechins group primarily consists of EGCG, ECG, EGC, and EC [10,11,12,13]. When considering the antioxidant activity of catechins, it is crucial to take into account both the total amount of hydroxyl groups as well as the distribution of those hydroxyl groups [16,19,20]. When compared with catechins that have a pyrogallol group, those that contain a catechol group are found to have a reduced antioxidant potential. However, the ability of catechins to act as antioxidants is dependent not only on their chemical composition but also on the circumstances in the surrounding environment [10,11,12,13,14,15,16,17,18].
3. Green Tea Catechins Health Beneficial Properties
Green tea contains a variety of beneficial polyphenols, in particular flavonols and flavanols, which are responsible for the tea’s positive effects on health. Experiments, both in vivo and in vitro, as well as clinical investigations, have shown that they have antioxidant, anti-inflammatory, and cardiovascular properties. Catechins are the predominant type of polyphenol found in green tea. The antioxidant properties of catechins are due to their ability to chelate metal ions (specifically copper ions) in redox reactions as well as to neutralize free radicals of oxygen. A number of human epidemiological and clinical studies on tea have revealed evidence for its chemopreventive effects, which have been validated by cell-based and animal investigations. Furthermore, specific chemical mechanisms underlying the action mechanism of EGCG and other catechins have been postulated. One of the most appealing methods is the involvement of reactive oxygen species (ROS). EGCG is known to have both antioxidant and pro-oxidant properties in regard to ROS [19,20]. The polyphenols found in green tea leaves have been shown in a number of scientific studies to have anti-tumor properties. These properties include the inhibition of cell division as well as the induction of phase II antioxidant enzymes. Some examples of these enzymes include superoxide dismutase, glutathione-S-transferase, glutathione peroxidase, and glutathione reductase. According to the literature, drinking green tea for a period of four months at a rate of four glasses per day can reduce the amount of 8-hydroxydeoxyguanosine found in the urine [30]. Numerous scientific studies in the fields of prostate, pancreatic, breast, and stomach cancers [14,15,16] have confirmed that the effects of green tea polyphenols on inhibiting the growth of cancer cells and reducing the risk of cancer can reduce the chances of developing cancer [14]. Green tea polyphenols have been shown to inhibit the growth of cancer cells [31]. Green tea may enhance chemotherapeutic as well as preventative benefits; however, it cannot replace the treatment provided by pharmaceuticals. This is an important point to emphasize. Notably, polyphenols, which include catechins, have the ability to trigger the death of cancer cells without damaging the surrounding healthy cells [9,14,17].
3.1. Action Mechanism of Green Tea Catechins
EGCG is the catechin derivative that has received the most attention to date. The amount of catechins that are present in a cup of green tea is mostly determined by the type of green tea, how it was grown, and how the leaves were processed, as well as how long it was brewed and at what temperature. According to a number of studies [9,10,11,12,13], catechins are at their most stable in an environment with a pH varying between 4 to 6. The research that is currently available suggests that catechins have a number of health benefits, including those that are anticancer [9], anti-inflammatory [32], anti-microbial [33,34,35], anti-viral [33,34,35], anti-diabetic [33,34,35], and cardiovascular [33,34,35]. It is important to underline the good effects that they have not only on bacteria but also on viruses, fungi, and prions [1].
The specific chemical structure of polyphenols found in green tea (the presence of a minimum of five hydroxyl groups) has a substantial impact on antioxidant capacity [19,20,39,40,41,42]. This is because green tea contains at least five hydroxyl groups. The di/tri-hydroxy structure of the B and D rings [39] as well as the meta-5,7-dihydroxy group at the A ring [1,43,44] make it possible for chelation of transition metal ions to occur [19,20]. For synthesizing any novel anticancer molecule(s) based on the structure of catechins, (i) the molecule should be of epicatechin type; (ii) it should have as many galloyl moieties as feasible as this would increase the number of hydroxyls capable of binding to DNA and Cu(II) and reducing it to Cu(I) [19]. Nevertheless, in particular circumstances, they might have effects that are pro-oxidative [19,20,45]. The regulation of catechins within an intracellular pool of nitro-oxidative stress is the primary mechanism by which these compounds exert their anticancer effects [46]. Therefore, polyphenolic chemicals, which bring health-promoting benefits for the body, can also result in the opposite consequences if very high dosages of catechins are utilized [47].
3.2. Green Tea Catechins’ Anticancer Potential
EGCG, which is known as the major polyphenol in green tea and contains eight different hydroxyl groups, is the most powerful bioactive component that green tea possesses [21,50,51]. In a prior study using an animal model of prostate cancer [50], the effect of catechins in inducing cell death was demonstrated and validated. There has been a lot of research done to confirm that EGCG can induce apoptosis and stop the cell cycle. One example of this would be in HCT-116 cells, which are used to study colon cancer [52,53]. It is widely recognized that the suppression of metalloproteinase activity by EGCG is the primary anticancer mechanism that it possesses. This idea has been given acceptance by a study that found a reduction in the number of metastases caused by prostate cancer following oral supplementation with catechins from green tea [46]. In an animal model of melanoma, catechols found in green tea were shown to limit the spread of cancer to the lungs [51]. In addition to this, there was revealed to be a positive correlation between the use of green tea and the risk of developing bladder cancer. There are additional studies that confirm the preventative role of green tea against colorectal adenomas after ingesting ten cups of green tea that are each 150 milliliters in size [51].
Breast cancer is one of the most common cancers found in females around the world. Research into the effects of green tea catechin derivatives, such as chemopreventive as well as synergistic effects along with chemotherapy, has been conducted on breast cancer cells in multiple trials in both the laboratory and clinically [51,55]. As a consequence, these catechins may have potential chemopreventive properties. At the moment, lung cancer is the most prevalent kind of cancer in the entire world. In the case of animal models (mice), it has been demonstrated that taking EGCG in oral supplement form has an effect on H1299 human non-small cell lung cancer xenografts. The findings of this research suggest not only an increase in the death of cancer cells by apoptosis but also a suppression of the growth of tumors in lung cancer [51,55,56]. In addition, the administration of EGCG in the form of an oral supplement promoted the production of reactive oxygen species in the mitochondria of lung cancer cells [51,55,56]. This may have occurred as a result of the low number of antioxidant enzymes present in these cells. It has been demonstrated that the addition of catechins generated from green tea to the medium used in cell culture causes an increase in the degree of oxidative stress, which ultimately results in apoptosis [50,57].
4. Signaling Pathways in Green Tea Catechins Anticancer Activity
The cell signaling pathways that are crucial for maintaining the equilibrium between cell proliferation and cell death have emerged as rational targets for anticancer therapies in recent years. As discussed, the catechins procured from green tea, specifically the most powerful EGCG, are able to trigger apoptosis in a variety of cancer models. In particular, it is able to trigger apoptotic pathways that are both intrinsic (using the mitochondria) and extrinsic (involving the death receptor) [76]. After being treated with catechols from green tea, cells exhibited several hallmarks of the apoptotic process, including nuclear condensation, caspase-3-activation, and cleavage of poly(ADP)ribose polymerase [77]. In addition, the activation of BAX, depolarization of mitochondrial membranes, and release of cytochrome c into the cytosol are all components of the anticancer mechanism that EGCG possesses [78]. The primary pathways utilized in the process of controlling cell proliferation are known as the induction of cell cycle arrest and apoptosis. As a matter of fact, catechols found in green tea have been shown to regulate both the G1/S transition and the G2/M transition in addition to preventing a rise in the number of cells and in DNA synthesis [76]. Most importantly, EGCG causes apoptosis (programmed cell death) and inhibition in the cell cycle in many cancer cells, while it does not have any effect on normal cells [12]. Research has shown that EGCG has the ability to directly block cyclin-dependent kinases [44], which is the primary event in the progression of the cell cycle. Additionally, EGCG lowers the expression of cyclin D1 and increases the phosphorylation of retinoblastoma [76]. This occurs despite the fact that it enhances the expression of p21 and p27. The molecular signaling pathways that are regulated by green tea catechols and that result in their pro-apoptotic and anti-proliferative effects include, among other things, suppression of nuclear factor kappa-B (NF-kB), which is the essential oxidative stress-sensitive transcription factor [14,51]. Inflammation, cell proliferation, and the death of cancer cells are just a few of the biological responses that are regulated by the transcription factor NF-kB, which plays an essential part in this process. In addition, endothelial nitric oxide synthase (eNOS) is stimulated by the catechins that are found in green tea, particularly the primary catechin known as EGCG [61,79].
The inhibition of mitogen-activated protein kinases (MAPKs), such as ERK, JNK, and p38, in the presence of EGCG, has been shown to have a favorable role in a wide variety of pathophysiological processes, including cell proliferation, differentiation, and the death of cancer cells [47,56,64,78]. In addition, it is well established that exposure to EGCG inhibits the action of tumor necrosis factor (TNF-α), which in turn causes cancer cells to undergo the process of apoptosis [60]. The suppression of the epidermal growth factor receptor (EGFR)-mediated signal transduction pathway is yet another event in the molecular signaling cascade that is affected by the catechols found in green tea. The epidermal growth factor receptor (EGFR) is a glycoprotein that is found in the plasma membrane. It contains an extracellular ligand-binding domain, a single transmembrane region, and an intracellular domain that possesses intrinsic tyrosine kinase activity. When tumor cells have an excessive amount of EGFR expression, they take on a neoplastic phenotype.
EGCG plays a leading role in the suppression or uncontrolled angiogenesis process, inhibiting the pro-angiogenic VEGF factors. High concentrations of EGCG have been shown to inhibit the production of VEGF in breast cancer cell lines [81]. It has been reported that EGCG inhibits the activity of VEGFR-2 [82]. Additionally, EGCG suppresses the activation of HIF-1 and NF-kB, as well as the expression of VEGF, hence inhibiting tumor angiogenesis and breast cancer growth. In addition, the results demonstrated that EGCG administration significantly decreased tumor weight compared to the control group and tumor VEGF expression [83]. By reducing the constitutive activation of Stat3 and NF-kB in cancer cells, EGCG decreases the synthesis of VEGF. EGCG targets the phosphoinositide-3-kinase (PI3K) and Akt/Protein Kinase B (PI3K/Akt) pathway. Despite the fact that the molecular mechanisms behind the combined action of autophagy and apoptosis have not yet been explained, a few studies have investigated the signaling pathways altered by EGCG. It has been demonstrated that EGCG induces apoptosis via the PI3K/Akt pathway [84].
5. Green Tea Catechins Anticancer Potential
Literature data strongly demonstrate that EGCG controls multiple molecular targets and inhibits the pathogenesis of cancer by preventing its initiation, development, and advancement. In addition, human clinical trials are still required to establish the efficacy of EGCG in the treatment of cancer. Multiple human clinical investigations show that EGCG has a role in cancer prevention. For the same purpose, clinical trials are now utilizing Polyphenon E (Poly E), a well-standardized decaffeinated green tea catechin combination that comprises 65% EGCG and EC [88].
EGCG was studied in stage III unresectable lung cancer. Radiation was given alongside cisplatin and etoposide. EGCG solution was administered three times a day at six concentration levels following grade II esophagitis. Dose escalation, oesophageal toxicity, and patient-reported discomfort were assessed weekly. EGCG was given in six dosage cohorts. All EGCG dosing tiers lacked dose-limiting toxicities. After radiotherapy, 22 of 24 patients had grade 0/I esophagitis, whereas 2 had degree 2 esophagitis. EGCG oral administration is practical, safe, and efficacious. The phase II recommended concentration of EGCG is 440 micromol/L [95].
6. Limitations of Using Green Tea Catechins as Anticancer Agents
Human epidemiological research has shown a link between consuming natural polyphenols and a lower risk of developing cancer. A typical polyphenol, EGCG, has been the subject of much research over the past several years that has examined its positive impact on health. The chemopreventive effect of EGCG depends on how well it is absorbed by the body and how well it interacts with target tissues. However, EGCG is thought to have low lipophilicity, which makes it less likely to pass through membranes, especially the intestinal epithelium [96]. Since it does not have a receptor-mediated transport, it is likely that the permeability of its membrane depends on passive diffusion [97]. Most of the time, a fairly high concentration of catechin is needed for EGCG to be useful as a medicine. For in vitro studies, an effective concentration of EGCG is usually between 1 and 100 mol/L. However, this value is hard to reach in in vivo conditions because the plasma peak of tea catechins is in the sub- or low-micromolar range [98].
Additionally, catechins do not absorb well, are unstable in the digestive tract, and are not very bioavailable. This makes it hard for them to reach the therapeutic target. Therefore, the fact that the biological effects of EGCG from in vitro and in vivo studies are not always the same is often due to the fact that it is not very stable. Under physiological conditions, catechins are quickly metabolized and changed into degradation products or pro-oxidant molecules, no matter how they are given [99,100].
This entry is adapted from the peer-reviewed paper 10.3390/ijms231810713
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