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GREEN TEA – IN CANCER TREATMENT

Tea is one the most widely consumed beverages in the world in the last 5000 years which was originally used as medicine. On the basis of leaf processing, tea leaves can be categorized into Green tea, Black tea and Oolong tea. These 3 types of tea leaves are produced from the leaves of the plant Camellia sinensis. Green tea is produced by steaming, panfrying and drying the Camellia sinensis leaves without fermentation whereas the black tea and oolong tea are fermented. Hence it can retain the important molecules such as polyphenols, which are said to be responsible for many health benefits.


Tea contains many polyphenols which are important constituents, including catechins and flavonoids. Green tea has high quantities of Green Tea Catechins (GTCs) when compared to any other type of tea. Amongst, all the major catechins in green tea, epigallocatechin-3gallate (EGCG), epicatechin-3-gallate (ECG), epigallocatechin (EGC), and epicatechin (EC) is the most abundant found, which constitute for about 70% of the entire catechin.


Table 1: Green Tea Catechins and their structures

Green Tea Catechins

Structures

(-)-Epicatechin



(-)-Epigallocatechin



(-)-Epicatechin-3-Gallate



(-)-Epigallocatechin-3-Gallate



Green tea is known to possess multiple health beneficiary properties such as:


Antioxidant and Pro-oxidant properties:

Green Tea Catechins (GTCs) possess antioxidant abilities by neutralizing free radicals. Among GTCs, ECG is said to have the greatest potency as a radical scavenger as compared to other catechins. Few studies indicate that GTCs exert a strong antioxidant function through suppressing free radical species and chelates transition metals. The antioxidant action is accredited to the presence of phenolic groups with sensitivity to oxidation which can generate quinine. The activity is further intensified due to the trihydroxyl structure in the D-ring. GTCs are believed to play their role as radical scavengers.


The direct antioxidant activity of tea catechins was found primarily under condition of tea catechins stress. GTCs can generate reactive oxygen species (ROS), which are required for the induction of apoptosis and lead to the obstruction of cancer cell growth. Both antioxidant and pro-oxidant activities of GTCs are thought to be significant against malignancy for cancer prevention, and to play roles in different aspects of the oncogenic process.



Induction of Apoptosis and Cell Cycle Arrest:

Cell cycle plays an important role in maintaining cell proliferation and tissue integrity. It is controlled in defined checkpoints by specific proteins and kinases that include cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors (CKIs) thoroughly. Deregulation of cell cycle and the cell cycle arrest are mostly responsible for cancer onset and progression.


Cyclin D1 is a protein necessary for progression through the G1 phase of the cell cycle. During the G1 phase, it is synthesized rapidly and accumulates in the nucleus, and is degraded as the cell enters the S phase. Cyclin D1 is considered as a regulatory subunit of Cyclin-dependent kinases (CDK4 and CDK6).


An inhibitor of cyclic-dependent kinase named p21 also acts as two-faced regulator depending on cell type, cell localization, p53 activity, and the type and level of genotoxic stress. It can acquire either onco-suppressive or onco-promoting properties depending on whether it is in a p-53 proficient or p-53 deficient environment, respectively.


Apoptosis (programmed cell death) has become a rapid and irreversible process for its ability to eliminate defective cells. Apoptosis can usually be executed in two ways: Mitochondria-mediated intrinsic pathway and death receptor-mediated extrinsic pathway. Cysteine-aspartate proteases (caspases) and the Bcl-2 family proteins such as Bax, Bcl-2 is also involved in these pathways. It is said that in pathological conditions such as cancer, alterations or mutations in the p53 gene are one of the main causes of apoptosis changes.


Studies have shown that EGCG ((-)-Epigallocatechin-3-Gallate) treatment influence apoptosis due to the generation of reactive oxygen species (ROS) and caspase-3 and -9 activations, leading to cell-cycle arrest at G1 phase through controlling expressions of cyclin D1, CDK4, and p21CIP1 (signalling pathway). Few other researchers have reported that EGCG ((-)-Epigallocatechin-3Gallate) reduced Bcl-2 and Bcl-xL protein levels and increased Bax with caspase-3 activation. It is observed that treatment with either EGCG or PolyE was observed to increase the ratio of cells in the G1 phase and to induce apoptosis. The treatment has been also reported to decrease cyclin D1 and Bcl-xL proteins and increase caspase-3 and -9 activities.


The results suggest that green tea and their constituents exert anticancer activity by regulating cell cycle arrest and inducing apoptosis through various mechanisms.



Fig. 1; Properties of Green Tea

Inhibition of NF-κB and AP-1:

Nuclear factor κB is a pro-inflammatory transcription factor that regulate the expression of different proteins—such as cytokines, interleukin-1 (IL1), interleukin-2 (IL-2), and interferon-γ (IFNγ)—involved in multiple cell signaling pathways associated with cancer progression and inflammation. NF-κB and IL-8, plays a crucial role in tumorigenesis and it could control the expression and function of numerous genes involved in cell proliferation, sustained angiogenesis, and evasion from apoptosis.

When NF-κB is activated, it is translocated into the nucleus, which leads to diverse gene expression associated with carcinogenesis and tumor progression, including cellular transformation, proliferation, invasion, metastasis, radio-resistance, chemo-resistance, and inflammation.


Transcription factor activator protein-1 (AP-1) regulates gene expression levels with respect to apoptosis and cellular proliferation. It is considered that AP-1 promotes proliferation through up-regulation of cyclin D1 gene expression and down-regulation of tumor-suppressor genes like p53 and p21CIP1. These factors suggest that inhibiting NF-κB and AP-1 pathways is one of the important mechanisms underlying the anti-cancer activity of GTCs.


Inhibition of Tyrosine Kinase Pathway:

Studies have shown that receptor tyrosine kinases (RTKs) play crucial roles in cellular proliferation and apoptosis and are targets proposed by GTCs for cancer prevention. RTKs and their downstream signals, including the Ras/extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways, regulate the expression levels of various target genes associated with proliferation and apoptosis. Binding of cytokines and growth factors as specific ligands to the extracellular domain of RTKs activate intrinsic tyrosine kinase which is said to induce phosphorylation of tyrosine residues, leading to the formation of docking sites for downstream targets. In this way, activation of cell-surface RTKs and downstream signaling pathways satisfy roles in the modulation of various important processes.


The PI 3-Kinase/Akt signaling pathway is involved in basic cellular processes like protein synthesis, proliferation and survival. It is activated and is followed by ligand binding to a range of receptors such as integrin receptors, receptor tyrosine kinases, cytokine receptors.


Pre-cancerous cells or cancer cells frequently display unsuitable activities or establish activation of RTKs through mutation and over-expression of genes. EGFR-The epidermal growth factor receptor is a member of the ErbB receptors family, a subfamily of four closely related RTKs:


· EGFR (ErbB-1).

· Human epidermal growth factor receptor (HER) 2 /neu (ErbB-2).

· Human epidermal growth factor receptor (HER) 3 (ErbB-3).

· Human epidermal growth factor receptor (HER)4 (ErbB-4).


A separate family of RTKs comprises of Insulin-like growth factor-1 receptor (IGF-1R) and VEGF receptor (VEGFR). Deformities in some RTKs, especially EGFR, VEGFR2, and IGF-1R, are associated with the properties of malignancy. These findings indicate that RTKs, such as EGFR and HER2, are targets in the prevention of cancer and therapy of malignancies. It is said that RTK modulators are used for the treatment of various types of cancer, such as lung, breast, stomach, and colon cancer.


Modulation of Immune System (Anti-Inflammatory property):

The immune system of the human body functions to fight against unusual conditions or abnormal agents in the body to prevent diseases. It is reported that Green tea has increased humoral and cell-mediated immunity, resulting in decreased risk of various types of cancers. Inflammation is regarded as one of the immune system responses, but inappropriate inflammation frequently causes various diseases. EGCG is known to have a strong anti-inflammatory effect with therapeutic potential and a large number of in-vivo studies suggest that green tea polyphenols administration resulted in attenuated inflammation.


Certain studies have suggested that GTCs administration may possess a favorable efficacy on inflammatory disorders through anti-inflammatory activity and inhibiting NF-κB activation.


A tryptophan catabolic enzyme indoleamine 2,3-dioxygenase (IDO) is thought to suppress effector T cell immunity and to play a crucial role in inducing immune tolerance. Observations in few studies indicate that EGCG appears to exert inhibitory effects on cancers by suppressing IDO expression and function, suggesting that IDO-inhibiting agents, including EGCG, have the potential for immunomodulation against malignancy of cancer.


Epigenetic Alteration:

Epigenetics is the reversible heritable alterations of gene expression, which do not involve alteration in DNA sequence. These employ notable changes in the regulation of gene expressions and contribute to cancer development due to their effect on histone modification, altering chromatin structure, and regulating non-coding microRNA expression. Epigenetics suppresses DNA-repair and tumor-suppressor genes, which usually results from gene hyper-methylation in the early stages of cancer, which is often related to various diseases.


EGCG has been reported to alter epigenetics in cancer cells through histone modification and DNA methylation. It was reported that EGCG suppressed DNA methyl transferase activation, leading to cytosine phosphate-guanine demethylation and to the following restoration of suppressed tumor-suppressor genes.


Anti-Metabolic Effects:

Metabolic syndrome consists of various medical disorder like obesity, high blood pressure, hyperglycaemia, and dyslipidaemia. It has been reported that GTCs have preventive effects against such medical disorders. Also, certain human intervention studies have shown anti-obesity effects of green tea. In these recent studies metabolic syndrome is recognized as a major risk factor for various types of cancer. GTCs are considered to possibly improve the condition of metabolic syndrome, which leads to prevention of carcinogenesis.


Intake:

Consuming too much caffeine can increase feelings of anxiety, interfere with sleep and can cause stomach upset and headaches in some people. Consuming large amounts of caffeine while pregnant may even increase the risk of birth defects and miscarriage. Based on certain research, everyone, including pregnant women, are advised not to consume more than 300 mg of caffeine daily.


The catechins in green tea may reduce your ability to absorb iron from food. Consuming catechins in large quantities may lead to iron deficiency, anaemia. Infants, young children, women who are pregnant or menstruating and individuals who have internal bleeding or are undergoing dialysis are all at an increased risk of iron deficiency. The catechins in green tea can also interfere with certain medications and decrease their effectiveness.


Toxic effects are most common when people take green tea supplements which have a much higher concentration of catechins than green tea itself.


Considering the above-mentioned facts, intake of green tea on a regular basis limiting to 2-3 cups a day would be good enough to absorb the beneficiary aspects from it. It is important to note that any sort of tea when mixed with milk, leads to a complex and inactivates the flavonoid component present in it making it to lose the antioxidant property.




Comments


GREEN TEA – IN CANCER TREATMENT

Tea is one the most widely consumed beverages in the world in the last 5000 years which was originally used as medicine. On the basis of leaf processing, tea leaves can be categorized into Green tea, Black tea and Oolong tea. These 3 types of tea leaves are produced from the leaves of the plant Camellia sinensis. Green tea is produced by steaming, panfrying and drying the Camellia sinensis leaves without fermentation whereas the black tea and oolong tea are fermented. Hence it can retain the important molecules such as polyphenols, which are said to be responsible for many health benefits.


Tea contains many polyphenols which are important constituents, including catechins and flavonoids. Green tea has high quantities of Green Tea Catechins (GTCs) when compared to any other type of tea. Amongst, all the major catechins in green tea, epigallocatechin-3gallate (EGCG), epicatechin-3-gallate (ECG), epigallocatechin (EGC), and epicatechin (EC) is the most abundant found, which constitute for about 70% of the entire catechin.


Table 1: Green Tea Catechins and their structures

Green Tea Catechins

Structures

(-)-Epicatechin



(-)-Epigallocatechin



(-)-Epicatechin-3-Gallate



(-)-Epigallocatechin-3-Gallate



Green tea is known to possess multiple health beneficiary properties such as:


Antioxidant and Pro-oxidant properties:

Green Tea Catechins (GTCs) possess antioxidant abilities by neutralizing free radicals. Among GTCs, ECG is said to have the greatest potency as a radical scavenger as compared to other catechins. Few studies indicate that GTCs exert a strong antioxidant function through suppressing free radical species and chelates transition metals. The antioxidant action is accredited to the presence of phenolic groups with sensitivity to oxidation which can generate quinine. The activity is further intensified due to the trihydroxyl structure in the D-ring. GTCs are believed to play their role as radical scavengers.


The direct antioxidant activity of tea catechins was found primarily under condition of tea catechins stress. GTCs can generate reactive oxygen species (ROS), which are required for the induction of apoptosis and lead to the obstruction of cancer cell growth. Both antioxidant and pro-oxidant activities of GTCs are thought to be significant against malignancy for cancer prevention, and to play roles in different aspects of the oncogenic process.



Induction of Apoptosis and Cell Cycle Arrest:

Cell cycle plays an important role in maintaining cell proliferation and tissue integrity. It is controlled in defined checkpoints by specific proteins and kinases that include cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors (CKIs) thoroughly. Deregulation of cell cycle and the cell cycle arrest are mostly responsible for cancer onset and progression.


Cyclin D1 is a protein necessary for progression through the G1 phase of the cell cycle. During the G1 phase, it is synthesized rapidly and accumulates in the nucleus, and is degraded as the cell enters the S phase. Cyclin D1 is considered as a regulatory subunit of Cyclin-dependent kinases (CDK4 and CDK6).


An inhibitor of cyclic-dependent kinase named p21 also acts as two-faced regulator depending on cell type, cell localization, p53 activity, and the type and level of genotoxic stress. It can acquire either onco-suppressive or onco-promoting properties depending on whether it is in a p-53 proficient or p-53 deficient environment, respectively.


Apoptosis (programmed cell death) has become a rapid and irreversible process for its ability to eliminate defective cells. Apoptosis can usually be executed in two ways: Mitochondria-mediated intrinsic pathway and death receptor-mediated extrinsic pathway. Cysteine-aspartate proteases (caspases) and the Bcl-2 family proteins such as Bax, Bcl-2 is also involved in these pathways. It is said that in pathological conditions such as cancer, alterations or mutations in the p53 gene are one of the main causes of apoptosis changes.


Studies have shown that EGCG ((-)-Epigallocatechin-3-Gallate) treatment influence apoptosis due to the generation of reactive oxygen species (ROS) and caspase-3 and -9 activations, leading to cell-cycle arrest at G1 phase through controlling expressions of cyclin D1, CDK4, and p21CIP1 (signalling pathway). Few other researchers have reported that EGCG ((-)-Epigallocatechin-3Gallate) reduced Bcl-2 and Bcl-xL protein levels and increased Bax with caspase-3 activation. It is observed that treatment with either EGCG or PolyE was observed to increase the ratio of cells in the G1 phase and to induce apoptosis. The treatment has been also reported to decrease cyclin D1 and Bcl-xL proteins and increase caspase-3 and -9 activities.


The results suggest that green tea and their constituents exert anticancer activity by regulating cell cycle arrest and inducing apoptosis through various mechanisms.



Fig. 1; Properties of Green Tea

Inhibition of NF-κB and AP-1:

Nuclear factor κB is a pro-inflammatory transcription factor that regulate the expression of different proteins—such as cytokines, interleukin-1 (IL1), interleukin-2 (IL-2), and interferon-γ (IFNγ)—involved in multiple cell signaling pathways associated with cancer progression and inflammation. NF-κB and IL-8, plays a crucial role in tumorigenesis and it could control the expression and function of numerous genes involved in cell proliferation, sustained angiogenesis, and evasion from apoptosis.

When NF-κB is activated, it is translocated into the nucleus, which leads to diverse gene expression associated with carcinogenesis and tumor progression, including cellular transformation, proliferation, invasion, metastasis, radio-resistance, chemo-resistance, and inflammation.


Transcription factor activator protein-1 (AP-1) regulates gene expression levels with respect to apoptosis and cellular proliferation. It is considered that AP-1 promotes proliferation through up-regulation of cyclin D1 gene expression and down-regulation of tumor-suppressor genes like p53 and p21CIP1. These factors suggest that inhibiting NF-κB and AP-1 pathways is one of the important mechanisms underlying the anti-cancer activity of GTCs.


Inhibition of Tyrosine Kinase Pathway:

Studies have shown that receptor tyrosine kinases (RTKs) play crucial roles in cellular proliferation and apoptosis and are targets proposed by GTCs for cancer prevention. RTKs and their downstream signals, including the Ras/extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways, regulate the expression levels of various target genes associated with proliferation and apoptosis. Binding of cytokines and growth factors as specific ligands to the extracellular domain of RTKs activate intrinsic tyrosine kinase which is said to induce phosphorylation of tyrosine residues, leading to the formation of docking sites for downstream targets. In this way, activation of cell-surface RTKs and downstream signaling pathways satisfy roles in the modulation of various important processes.


The PI 3-Kinase/Akt signaling pathway is involved in basic cellular processes like protein synthesis, proliferation and survival. It is activated and is followed by ligand binding to a range of receptors such as integrin receptors, receptor tyrosine kinases, cytokine receptors.


Pre-cancerous cells or cancer cells frequently display unsuitable activities or establish activation of RTKs through mutation and over-expression of genes. EGFR-The epidermal growth factor receptor is a member of the ErbB receptors family, a subfamily of four closely related RTKs:


· EGFR (ErbB-1).

· Human epidermal growth factor receptor (HER) 2 /neu (ErbB-2).

· Human epidermal growth factor receptor (HER) 3 (ErbB-3).

· Human epidermal growth factor receptor (HER)4 (ErbB-4).


A separate family of RTKs comprises of Insulin-like growth factor-1 receptor (IGF-1R) and VEGF receptor (VEGFR). Deformities in some RTKs, especially EGFR, VEGFR2, and IGF-1R, are associated with the properties of malignancy. These findings indicate that RTKs, such as EGFR and HER2, are targets in the prevention of cancer and therapy of malignancies. It is said that RTK modulators are used for the treatment of various types of cancer, such as lung, breast, stomach, and colon cancer.


Modulation of Immune System (Anti-Inflammatory property):

The immune system of the human body functions to fight against unusual conditions or abnormal agents in the body to prevent diseases. It is reported that Green tea has increased humoral and cell-mediated immunity, resulting in decreased risk of various types of cancers. Inflammation is regarded as one of the immune system responses, but inappropriate inflammation frequently causes various diseases. EGCG is known to have a strong anti-inflammatory effect with therapeutic potential and a large number of in-vivo studies suggest that green tea polyphenols administration resulted in attenuated inflammation.


Certain studies have suggested that GTCs administration may possess a favorable efficacy on inflammatory disorders through anti-inflammatory activity and inhibiting NF-κB activation.


A tryptophan catabolic enzyme indoleamine 2,3-dioxygenase (IDO) is thought to suppress effector T cell immunity and to play a crucial role in inducing immune tolerance. Observations in few studies indicate that EGCG appears to exert inhibitory effects on cancers by suppressing IDO expression and function, suggesting that IDO-inhibiting agents, including EGCG, have the potential for immunomodulation against malignancy of cancer.


Epigenetic Alteration:

Epigenetics is the reversible heritable alterations of gene expression, which do not involve alteration in DNA sequence. These employ notable changes in the regulation of gene expressions and contribute to cancer development due to their effect on histone modification, altering chromatin structure, and regulating non-coding microRNA expression. Epigenetics suppresses DNA-repair and tumor-suppressor genes, which usually results from gene hyper-methylation in the early stages of cancer, which is often related to various diseases.


EGCG has been reported to alter epigenetics in cancer cells through histone modification and DNA methylation. It was reported that EGCG suppressed DNA methyl transferase activation, leading to cytosine phosphate-guanine demethylation and to the following restoration of suppressed tumor-suppressor genes.


Anti-Metabolic Effects:

Metabolic syndrome consists of various medical disorder like obesity, high blood pressure, hyperglycaemia, and dyslipidaemia. It has been reported that GTCs have preventive effects against such medical disorders. Also, certain human intervention studies have shown anti-obesity effects of green tea. In these recent studies metabolic syndrome is recognized as a major risk factor for various types of cancer. GTCs are considered to possibly improve the condition of metabolic syndrome, which leads to prevention of carcinogenesis.


Intake:

Consuming too much caffeine can increase feelings of anxiety, interfere with sleep and can cause stomach upset and headaches in some people. Consuming large amounts of caffeine while pregnant may even increase the risk of birth defects and miscarriage. Based on certain research, everyone, including pregnant women, are advised not to consume more than 300 mg of caffeine daily.


The catechins in green tea may reduce your ability to absorb iron from food. Consuming catechins in large quantities may lead to iron deficiency, anaemia. Infants, young children, women who are pregnant or menstruating and individuals who have internal bleeding or are undergoing dialysis are all at an increased risk of iron deficiency. The catechins in green tea can also interfere with certain medications and decrease their effectiveness.


Toxic effects are most common when people take green tea supplements which have a much higher concentration of catechins than green tea itself.


Considering the above-mentioned facts, intake of green tea on a regular basis limiting to 2-3 cups a day would be good enough to absorb the beneficiary aspects from it. It is important to note that any sort of tea when mixed with milk, leads to a complex and inactivates the flavonoid component present in it making it to lose the antioxidant property.




Comments


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