Sunday, 14 January 2018

The Science of Tea: Green Tea in Risk of Cancers

Kyle J. Norton

The use of plants for healing purposes has been predated long before the existence of modern medicine. Herbal plants have formed a fundamental source for conventional medicine in discovery of single ingredient medication, including aspirin (from willow bark), quinine (from cinchona bark), and morphine (from the opium poppy)......

Green tea, a precious drink processes numbers of health benefit known to almost everyone in Asia and Western world. However, as yin in nature herbal medicine or food, long term injection of large amounts may obstruct the balance of yin-yang, induced "yin excessive syndrome" or "yang vacuity syndrome" including weaken immunity and painful case of GERD,... according to traditional Chinese medicine's Yin-Yang theory. Adding a slice of ginger will do the trick.

Cancers are class of chronic medical conditions characterized by abnormal cell growth disorderly and uncontrollably in some specific tissues.  At the later stage, the malignant cells have a tendency to spread to other tissue distance away from the originated site.

Epidemiological studies strongly suggested that green tea and its bioactive chemical constituents, particularly, Epigallocatechin-3-gallate (EGCG) may have potential and therapeutic implications in reduced risk of various types of cancer(1-49). However, geographic differences where the tea are growth, types of tea, time of harvest, time of feeding, how the tea are fermented,.....may effect the quality of tea in prevention of tumor onset.

1. Breast Cancer
Breast cancer (malignant breast neoplasm) is a cancer that starts in the tissues of the breast either from the inner lining of milk ducts (Ductal carcinoma) or the lobules (Lobular carcinoma) that supply the ducts with milk. there is also rare cases that breast cancer starts in other areas of the breast.

According to the joint study lead by the Xinyang Normal UniversityHenan, Epigallocatechin-3-gallate (EGCG), a bioactive compound in green tea inhibited risk of breast cancer through many mechanisms involving primarily in cell death and survival(1).

In MDA-MB-231 breast cancer cell line, epigallocatechin gallate isolated from green tea induced apoptosis and inhibited tumorigenesis(2) through expression of multiple signaling pathways in breast cancer cells.

 EGCG decreased MDA-MB-231 cell viability and significantly down regulated the expression of β-catenin(2) in regulated the coordination of cell–cell adhesion and gene transcription, according to Western blot analysis as patients with breast cancer is found to associate to high levels of β-catenin in breast cancer tissue than in normal tissue.

Dr. Hong OY, the lead author said, "EGCG inhibits the growth of MDA-MB-231 cells through the inactivation of the β-catenin signaling pathway(2). Based on these promising results, EGCG may be a potential treatment for triple negative breast cancer patients.".

In polychlorinated biphenyls (PCBs) accumulated in human breast cancer tissue induced the growth of estrogen-sensitive tumors, EGCG inhibited the early onset of breast cancer through modifying estrogenic activity against cell proliferation in a dose-dependent manner(3).

At dose of at 25 μM, EGCG also exerted antiproliferative and pro-apoptotic action in activation of ERβ receptor(3) to interact with or inhibit ERα in suppressed breast cancer cell growth.

2. Prostate Cancer
According to the Fu Jen Catholic University, New Taipei City, catechin nanoemulsion preparation showed a highest inhibition of growth of PC-3 tumor cells, with concentration being 15.4 μg/mL and 8.5 μg/mL(4).

The inhibition of prostate cancer cell line is observed in cell cycle arrest by regulated proteins involved cell cycle division(4), namely cyclin A, cyclin B, cyclin-dependent kinase 2, and cyclin-dependent kinase 1 expression and activated cell atopotosis and survival.

Dr. Tsai YJ, the lead author said, "Catechin extract and nanoemulsion could induce apoptosis of PC-3 cells through decrease in B-cell lymphoma 2 (bcl-2) expression and increase in cytochrome c expression( in induction of apoptosis) for activation of caspase-3, caspase-8, and caspase-9 (involved cell death)".

In the recruited 404 PCA cases and 395 controls from the same hospital to investigate whether habitual tea consumption, including green, oolong, black and pu'er tea regular green drinkers have a significantly reduced risk in prostate cancer development(5), scientists found that there are inverse relation of tea drinkers and risk of prostate cancer among the habitual pu'er tea drinkers(6)and lower intake of EGCG(5) was observed among cases (54.4 mg) than the controls (72.5 mg).

The differentiation of 7 observational studies and 3 randomized controlled trials retrieved from Cochrane Library, PubMed, Sciencedirect Online, and hand searching.the database, also revealed an interest correlated incidence of PCa decrease with each cup/day increase of green tea(6)..

According of the study(6), "higher green tea consumption was linearly reduced PCa risk with more than 7 cups/day and green tea catechins were effective for preventing PCa".

3. Osteosarcoma
Osteosarcoma is a medical condition of bone cancer characterized by producing immature bone and occurred mostly in children and young adults between the ages of 10 and 30.

According to the study in investigation of the effects of Epigallocatechin-3-gallate (EGCG), in reduced risk of osteosarcoma expression in compared to miR-126 in the proliferation, invasion, migration, and chemotherapeutics resistance in cancer(7), application of Epigallocatechin-3-gallate (EGCG) exerted a significant effect in suppresseed proliferation of human cell line osteosarcoma MG63 and U2OS cells in a concentration-dependent and time-dependent manner and inhibited cancer cell lines at the concentration of 0.05 g/L on U2OS cells equivalent to 20 μM cisplatin (DDP)(7)

In compared to green tea extract induced cell death by interfering in cell cycle arrest, miR-126, the chemo suppressor drug induced apoptosis and inhibited proliferation in U2OS cell line but without significant effects on phase 1 of cancerous cell cycle division(7).

Researchers suggested application of Epigallocatechin-3-gallate (EGCG) may increase the effect of tumor suppressing drug miR-126 and for treatment of osteosarcoma(7).

The inhibition of miR-126 osteosarcoma cells without inducing apoptosis and cells proliferation in cell cycle division(7) is attributed to the extract in target of sequences in reducing the expression of the targeted genes.

In other words, the extract can bind directly to inhibit DNA transcription and prevented mRNA in transmitting such transcription in initiated cancer development.

Other researchers suggested that the inhibition of Epigallocatechin-3-gallate (EGCG) in reduced cancerous cell death does not limit to the function of cell cycle arrest(8).

The phytochemical compoud also expressed the apoptotic effect through modulating gene expression of cancer cell line and induced degradation of cancerous cellular structure(8).

Additional evaluation of the phytochemical Epigallocatechin-3-gallate (EGCG) and the tumor suppressed drug miR-1 effect in osteosarcoma, researchers also found that Epigallocatechin-3-gallate has a profound and positive effect in improved the efficacy of miR-1 in induced cell apoptosis and proliferation observed in cancer cell lines MG-63 and U-2OS(8).

MG-63 and U-2OS treated by miR-1 and Epigallocatechin-3-gallate (EGCG) decreased c-MET expression, which is an indication of cancers development(8).

The combined application of Epigallocatechin-3-gallate (EGCG) and c-MET inhibitor (crizotinib) also displayed a significant inhibition of MG-63 and U-2OS cancer cell proliferation)8).

In the study of the effects of Se-enriched Ziyang green tea, containing chemical compound mannose, rhamnose and fucose in anti tumor activity on human osteosarcoma U-2 OS cells in vitro and in vivo, researchers found that Se-ZYTP at concentration of 25, 50, 100 and 200 μg/ml exerted a significantly inhibition of proliferation of human osteosarcoma U-2 OS cells in a concentration-dependent fashion(9).

In cancer cell line In U-2 OS cancer induced in BALB/c athymic mice model, Se-ZYTP oral administration at three doses of 100, 200 and 400mg/kg body weight (B.W.) daily for 28 days resulted in tumor regression as compared to model control without causing any serious side effects(9).

The illustration suggested that other chemical compounds found in green tea may also have the potential in suppression of proliferation and induced apoptosis of osteosarcoma.

The anti osteosarcoma activities of Se-enriched Ziyang green tea may be attributed to the stimulation in increased pro-apoptotic protein Bax expression(9)(upregulated by the tumor suppressor(9) protein p53 in induced apoptosis) and decreased expression levels of anti-apoptotic protein Bcl-2(9)(regulator proteins that regulate cell death) and NG2(9)(involved cell survival, migration and angiogenesis), some researchers suggested.

4. Lung Cancer
Lung cancer is a medical condition characterized by cells growth disorderly and uncontrollably of lung tissues. 

In the study to investigate the anti lung cancer effect of Epigallocatechin-3-gallate (EGCg), the major polyphenolic compound present in green tea, after taking into account of other con founders, researchers at the joint study lead by the Kyushu University of Health & Welfare, suggested that
the phychemical induces apoptosis of lung cancer through suppression of cell division, in cell culture(10).

In human A549 human non-small-cell lung cancer cell line, EGCg inhibited cancerous cell proliferation by interfering mRNA expression in modulation of apoptotic cell death(10) 

Additionally, application of 100 μM EGCg for 24 h. exhibited cancerous morphological changes, thus reducing cell proliferation(10).

The study also revealed that the efficacy of EGCg inhibited B-cell lymphoma-extra large (Bcl-xL)(10) through expression of mRNA and suppression of gene in related to cell death.

 Epigallocatechin-3-gallate (EGCg) in inhibited gene expression in risk of lung cancer by binding HIF-1α, in promoted cell proliferation and anchorage-independent growth, researchers launched a study to elucidate the role of microRNA in the EGCG inhibition of tobacco carcinogen-induced lung tumors in A/J mice found that 26 potential targeted genes of the 21 microRNAs. with the mRNA expression profiles may have some implications in increased lung cancer risk(11).

Application of EGCg, indeed, demonstrated a significant effect in improved cell regulation and reduced cell proliferation through many mechanisms, including regulation of AKT pathway(11) in promoted survival and growth in response to extracellular signals and NF-κB expression(11) in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation and MAP kinases(11), involved variety of fundamental cellular processes such as proliferation, differentiation, motility, stress response, apoptosis, and survival.

In other words, Epigallocatechin-3-gallate (EGCg) effect reduced risk and treatment of lung cancer is attributed to the inhibition of expression of RNA in transmitting information to proteins with function to initiated cancer cell change, including cell proliferation and apoptosis.

The findings also suggested that green tea Epigallocatechin-3-gallate (EGCg) has a strong effect in reduced risk lung cancer through both expression of mutate and cancer-related genes(11).

Mutated genes expression has been identified in contribution to cancer development and progression, therefore by target the expression of such genes may help scientists in explore the origins of abnormal gene expression in compared to normal cells.

Other researchers suggested that by targeting both DNA and RNA data to identify alternative expression of mutated gene in patients of lung cancer may open the door by offering specific treatment only for such patients.

More precisely, by identified such gene in cancer cell patients, scientist may prescribe gene targeting technology, specific medication and treatment to stop cancer from growing and spreading.

Further differentiation of the effect of green tea extract in lung cancer risk, researchers at the University in Toruń indicated that green tea extract catechins demonstrated a significant effect in inhibition of lung cancer line A549(12) independent to doses applied and increased cell and marker of cell degradation(12) and green tea extract catechins also expressed a strong protective effect in reduced self cause of toxicity(12)

This illustration indicated that green tea extract catechins exert anti lung cancer progression activity through protection against destruction and damage of redundant cellular components occurring in vacuoles within the cell without induced side effects.

5. Ovarian Cancer
In the analysis of the EGCG effects on 8 ovarian cancer cell lines (SKOV3, CAOV3, OVCAR3, OVCAR10, A2780, CP70, C30, and C200) and showed IC50s for EGCG at the micromolar range, researchers found that EGCG inhibited all ovarian cancer cell lines in dose depending manner(13).

Normal dose application of EGCG displayed a significant increase of antioxidant in reduced ROS over expression(13) of oxidative stress in inhibited ovarian cancer through cell cycle arrest in G2/M phase(13).

Administration of EGCG at common dose not only demonstrated a 6 fold increase of cisplatin potency for treatment of SKOV3, CAOV3, and C200 cells, but also attenuated the chemodrug toxicity(13).

However, the effect of EGCG on the formation of reactive oxygen species (ROS) was biphasic.
The phytochemical was shown to induce and decrease ROS formation in different doses.

Therefore, higher dose of EGCG promoted over expression of antioxidants in reduced oxidative stress may amplify the toxicity in ameliorated human cancer cells proliferation and induced apoptosis.

Dr.Bae KH, the lead author(13) said, "EGCG may accentuate oxidative stress to inhibit growth of ovarian cancer cells and sensitize them to cisplatin".

Other researchers in the study of toxicity of EGCG suggested that green tea catechin, (-)-epigallocatechin-3-O-gallate (EGCG) as a potent adjuvant to enhance the anti tumor efficacy of cisplatin while mitigating its harmful side effects through various mechanisms.

Application of EGCG showed to promote hyaluronic acid function in regulation of normal cell division and prevention of the acid in initiation of cancerous cell proliferation(14).

Hyaluronic acid, a polysaccharide molecule, plays an important role in cell proliferation and migration, and may involve in the progression of some malignant tumors.

Additionally, EGCG also expressed anti cancer effect by promoting the injection of chemo medicine cisplatin into the CD44-over expressing(14) cancer cells to prevent over growth of tumor cells.

In regard to toxicity, EGCG on one hand, reduced capacity of oxidative stress in initiated toxicity against off-target organs and tissues through induction of significant antioxidant activity(14) on the hand, and stimulated function of toxicity originating from cisplatin into the target tumors.

Green tea catechin-based micellar nanocomplexes also inhibited superiorly against tumor growth with no injection of cisplatin(14) and expressed a significant inhibition without induced toxicity in both cancer cells suspended in culture medium and injected into the animal models and peritoneal metastatic model of human ovarian cancer(14).

In other words, green tea catechin-based micellar nanocomplexes may be considered as a safe and effective cisplatin nanomedicine for ovarian cancer treatment..

In the additionally examined the effect of EGCG in suppressing ovarian cancer cell growth in 3 human ovarian cancer cell lines (p53 negative, SKOV-3 cells; mutant type p53, OVCAR-3 cells; and wild type p53, PA-1 cells),

EGCG decreased tumor growth in each cell line in a dose-dependent fashion and induced apoptosis and cell cycle arrest, particular to the G(1) phase in SKOV-3 and OVCAR-3 cells in compared to G(1)/S transition phase arrest in PA-1 cells(15).

The chemical also acted differentiately in upregulated the expression of genes and proteins in promoted cancer cell arrest, suppressed tumor growth and induced cell death(15) (Bax, p21, Retinoblastoma, cyclin D1, CDK4, Bcl-X(L)) by more than 2-fold.

6. Melanoma 
Melanoma, is a medical condition characterized by irregular cell growth of pigment-containing cells known as melanocytes.

According to the study, approximately 7,200 Canadians will be diagnosed with melanoma skin cancer.

In the review of literature published online, green tea bioactice EGCG significantly inhibited the growth, migration and invasion of melanoma cells through numbers of mechanism.

Gene implications in initiated cancer development and cancerous cells proliferation have gone through extensive research, particularly in melanoma.

In melanoma, green tea biactice EGCG demonstrated a significant effect in knockdown gene over expression (TRAF6)(16) in reduced migration and invasion of melanoma.

TRAF6 is a protein with function in activation of IkappaB kinase (IKK) in response to inflammation.
Green tea biactive EGCG directly bound to TRAF6 in melanoma in attenuated the interaction of
between TRAF6 and UBC13(E2) in activated the protein(16) (IkappaB kinase (IKK)) in production of pro inflammatory cytokins.

The ubiquitin-conjugating enzyme(UBC13(E2)) are essential in activation protein (NF- kappa B) in controls transcription of DNA, cytokine production and cell survival.

The phytochemicals also suppressed the TRAF6 E3 ubiquitin ligase activity of the tumor generated by TRAF6(16) in regulation of important biological processes, particularly, in cell division and for the survival of the tumors.

Green tea biactice EGCG also regulated the gene expression of proteins (IκBα and p-TAK1 e) in modulated and inactivated NF-κB-directed gene expression(16) of inflammation, immunity, cell proliferation, differentiation, and survival in melanoma.

Dr. Zhang J(16), the lead author said, "EGCG is a novel E3 ubiquitin ligase inhibitor that could be used to target TRAF6 for chemotherapy or the prevention of melanoma".

Other researchers in focus of Green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG) effect in attenuated and treatment of melanoma in the gene implication via MicroRNAs (17)(miRNAs, non-coding RNAs involved in various biological processes by regulating their target genes) also indicated that green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG) inhibited melanoma tumor growth by activating 67-kDa laminin receptor (67LR) signaling(17) which has an function in down regulated tumor cell proliferation and tumor formation by inducing apoptosis.

The bioactive compound also up-regulated miRNA-let-7b expression in induced tumor suppressor function in decrease function of 67LR in enhanced invasive and metastatic melanoma cells.

Indeed, green tea EGCG-also displayed a significant effect in promote function of let-7b in altering the traits,of malignant cell in melanoma through regulating the expression of HMGA2.with action as DNA transcriptional regulator(17).

Green tea EGCG. also induced expression of let-7b in inhibitions of oncoproteins and activation of tumor suppressor via tumor-over expressed 67LR in activation of PP2A(17), a tumor suppressor. through adenylate cyclase/cAMP pathway in cell communication.

In compared the effects of TNF-related apoptosis-inducing ligand (TRAIL), a protein with function in in induced tumor cells apoptosis. and green tea bioactive EGCG effects in  A375 melanoma cell line, researchers found that TRAIL application group demonstrats a strong effect in inhibition with apoptosis rate was 11.8% at dose of 150ng/mL in compared to green tea EGCG treatment group of 5%-7%(18).

In combined TRAIL and green tea EGCG treatment groups, the inhibited rate increased sufficiently to 48.9 - 59.1%(18) and EGCG effective in treatment of melanoma was attributed to activity of caspase-3 rather than caspase-8 in mediation of programmed cell death (apoptosis)(18).

7. Liver Cancer
In liver cancer animal model induced by chronic exposure of N-nitrosodiethylamine (NDEA), a carcinogenic and mutagenic organic compound, application of green tea bioactive compounds Epigallocatechin gallate (EGCG) and Theaflavin (TF) demonstrated a strong effect in reduced initiation of cancer formation(19) and potential chemopreventive effect in pre and post treatment(19) of the injected animal.

 EGCG/TF action in restrain the over expression of liver cancer cells  proliferation was the result of modulated similarly to those of CD44-specific cell membrane binding combined with near-infrared irradiation in induction of cellular apoptosis(19).

High CD44-positive expression is found to associate to acute cancer cells killing.

The restriction processes of EGCG/TF in modification of onset of liver cancer development, was also found to modify multiple biogenesis involved maintaining a relatively stable equilibrium in organs tissues(self-renewal Wnt/β-catenin, Hh/Gli1 pathways)(19) in gene with implication of cell cycle progression, apoptosis and cellular transformation and cell differentiation and proliferation(Cyclin D1, cMyc and EGFR)(19) and tumor suppressor (E-cadherin)(19) during the carcinogenesis processes.

The therapeutic efficacy of tea polyphenols epigallocatechin gallete (EGCG) and theaflavin (TF) also regulated the proteins expression of cell differentiation, polarity and proliferation(the self-renewal Wnt and Hedgehog (Hh) pathways(20).during CCl4/N-nitosodiethylamine-induced mouse liver carcinogenesis.

Green tea bioactive tea polyphenols epigallocatechin gallete (EGCG) and theaflavin (TF) induced chemo preventive potential in maintain cell integrity at the 30 weeks of CCl4/N-nitosodiethylamine application.

Continuous administration of EGCG/TF exerted a strong impact in reduced proliferation and increased apoptosis(20), as well as decreased function of hepatic progenitor cells (HPCs)(20) in participated restoration of the cancerous liver tissue and population with cancer stem cell-like characteristics in liver carcinoma observed by AFP and CD44 expression(20).in CCl4/N-nitosodiethylamine-induced mouse liver carcinogenesis.

During the restriction processes of EGCG/TF, the bioactive compounds also modulated the expression of tumor progression to a more invasive phenotype(20)(phospho-β-catenin-Y-654), tumor suppressor(β-catenin)(20), the proliferation, migration and invasion of liver cancer gene(sFRP1 )(20) and gene in control tumor suppressor(β-catenin)(20).

In other words, green tea EGCG/TF inhibited the contaminated cells inflicted by injection of CCl4/N-nitosodiethylamine to prevent the initiation of liver cancer through modulation of certain gene expressions involved in liver cancer progression.

In short, the inhibition of liver carcinogenesis by EGCG/TF was attributed to reduction in hepatocyte progenitor cell and stem cell population by restoring liver cancerous cells damage through various mechanisms indicated above.

8. Gastric Cancer
According to medical literature published online, in vascular endothelial growth factor (VEGF) over expression in formation of new blood vessel to provide nutrients and fluids for the survival of gastric cancer, application of green tea (-)-Epigallocatechin-3-gallate (EGCG) restricted the pro-inflammatory cytokine interleukin-6 (IL-6)(21) induced VEGF(21) in stimulated signal protein in transmitted alternated DNA transcript and activated suppression of anti cell apoptosis transcription 3 (Stat3)(21).

Oral administration of green tea extract decreased levels of IL-6, VEGF overexpression in doses depending manner.

In compared to healthy individual, IL-6, VEGF expression were found to increase more than 2.4-fold in patients with gastric cancer(21).

The chemical compound also exhibited anti cancer progressive activity by blocking the process of complex sequence of VEGF expression in transferring faulty DNA transcription to signal proliferation of cancer cells through mRNA in protein synthesis.

In other words, green tea inhibited the progression of cancer development induced by over expression of vascular endothelial growth factor (VEGF) was total depended EGCG's DNA biding activity(21) and inhibition of Stat proteins(21) in differentiated cytoplasm into the nucleus, the important step in initiation of cancer progression.

According to experiments in vitro and vitro, EGCG also expressed a significant effect in the reduced the IL-6 properties in stimulated vascular endothelial cells in promoted cancer cells proliferation and formation.

After taking into account of other con founders, Dr. Zhu BH, the lead author(21) said, "EGCG inhibits IL-6-induced VEGF expression and angiogenesis via suppressing Stat3 activity in gastric cancer, which has provided a novel mechanistic insight into the anti-angiogenic activity of EGCG".

Additionally, researchers in further illustration of the effect of EGCG (0, 5, 10, 25 or 50 μmol/L), in human gastric cancer cells (AGS) caused by IL-6 (50 μg/L) suggested that interleukin 6 (IL-6)over expression not only significantly increased VEGF expression in AGS gastric cancer cells, but also increased function of mRNA expression by more than 2.4 fold(22) in the process to initiated tumor development, in dose depending manner.

Treatment of bioactive EGCG with doses of 0, 5, 10, 25 or 50 μmol/L demonstrated a therapeutic activities in reduced the release protein of VEGF to stimulated and mRNA expression of alternated transcript.

In compared to AG490, a Stat3 pathway inhibitor used for treatment of gastric cancer, green tea EGCG blocked the sequence of transcript transferred step in induced expression of pSTAT3(22) in proliferation of cells and tumor tissues without causing change in STAT3 gene(22).

In 5-FU resistance of GC SGC7901/FU and MGC803/FU, gastric cancer cell lines, injection of epigallocatechin gallate (EGCG) displayed a significantly suppressed the proliferation and tumor growth through reversed the 5-FU(23) resistance of GC cells via inhibited the P-glycoprotein 1 (MDR1)(23) and P-glycoprotein (P-gp)(23) also known as multidrug resistance proteins in transmitted transcript in obstructing cell internalization of chemotherapeutic agents and developing transporter mediated resistance by cancer cells during anti-tumor treatments.

8. Colon Cancer
According to the study by the University College of Medicine, Seoul, application of EGCG on HT-29 colon cancer cells showed a significant effect in inhibition of cell cycle progression of protein in COX-2 expression(24) through activation of AMPK activity(24) in promoted metabolic tumor suppressor by regulating energy levels, enforcing metabolic checkpoints and inhibiting cell growth.

Cyclooxygenase(COX)-2, is an enzyme with function in speeding up the production of hormone prostaglandins in regulated cell proliferation and cell apoptosis.

AMPK(5' AMP-activated protein kinase) plays a role in cellular energy homeostasis, activation of AMPK(24) may result in tumor growth inhibition, cell cycle arrest, and apoptosis of cancer cells in some tumor types/contexts.

In inhibition of COX-2 expression, green tea EGCG reduced prostaglandin E(2) secretion(24), thus reducing risk of the hormone)(24) in modulated angiogenesis, including the process of new blood vessel formation, promoted proliferation, migration and formation of endothelial cells, lining the interior surface of blood vessels and lymphatic vessels.

The study also emphasized that inhibiting AMPK by an AMPK inhibitor may interrupt the function of the bioactive compound in initiated such changes(24).

Continuously, the activation of enzyme AMPK also had a strong implication on VEGF(24) (vascular endothelial growth factor) and glucose transporter in facilitated Glut-1(24) in  transport of glucose across the plasma membranes of mammalian cells in EGCG-treated cancer cells.

Application of EGCG activated AMPK enzyme also modulated the production of ROS without causing ROS expression in initiated tumor progression and damage to cellular structures(24), such as the lipid membrane, protein and nucleic acid but inducing cancer cells DNA mutations and compromised genome integrity, subsequently in cancer cells senescence and death.

In other aspect of study of colon cancer in animal model, diminished levels of retinoid X receptor-alpha (RXRα) in regulated cancer cell growth and modulated suppress tumorigenesis may have a profound effect in cell proliferation.

Application of green tea bioactive EGCG expressed a significant effect in restored RXRα protein and expression levels caused by methylation function in alternated the activity of a DNA segment(25) without changing the sequence, thus reducing risk of cancer expansion.

Additional differentiation also suggested that EGCG induced methylation changes in several other colon cancer related genes to restore the levels of RXRα without causing a decrease in global methylation(25) in maintaining the epigenetic state of individual genes.

Change of globe methylation expression is found to associate to the occurrence of cancer.

Retinoid X receptor-alpha (RXRα) is a nuclear receptor with function in regulated cancer proliferation and modulated suppression of tumorigenesis.

9. Lymphoma
In EL4 cancer cells line, injection of green bioactive saponin stimulated the immunomodulatory activity in inhibited EL4 cells line through regulated cytokine expression induced by inflammation and mitogen-activated protein kinases (MAPK) signaling pathway(26) involved in a variety of fundamental cellular processes such as proliferation, differentiation, motility, stress response, apoptosis, and survival.

Furthermore, injected saponin also reduced the expression of EL4 cells line in tumor proliferation by interrupting the process of sequence of mutated DNA transcript in mRNA expression in transmitting transcript by initiating production of inflammatory cytokines to reverse transcription polymerase chain reaction in making copies of alternated gene(26), thus attenuating risk of tumor growth, tumor progression and immuno-suppression, activities in host anti-tumor response.

Treatment of green tea saponin also was found to induced cytotoxicity to EL4 cancer cell line without causing harm to healthy cells.

The efficacy of tea saponin in inhibition of the proliferation and invasiveness of T-lymphoma (EL4) cells, may be attributed to the effect of others inflammatory cytokines such as tumor necrosis factor alphaTNF-α(26)in induced cancer cells death and NF-κB(26) in controlled transcription of DNA, cytokine production and cell survival through mediated the regulation of MAPK pathway(26) in transduction (process by which foreign DNA is introduced into a cell by a virus or viral vector) and extracellular signals to cellular responses in induction of cell proliferation, differentiation, development, transformation, and apoptosis.

Tumor necrosis factor alpha TNF-α, a pro-inflammatory cytokine plays an important role in the acute phase of inflammation with function in regulation of  biological processes of cell proliferation, differentiation and apoptosis.

Nuclear factor-κB (NF-κB) is a transcription factor with function in regulated expression of genes involving many biological processes including innate and adaptive immunity, inflammation and stress responses,

In NOD/SCID mice transplanted intraperitoneally with human non-Hodgkin's lymphoma (NHL) cell lines Namalwa, RAP1-EIO and HS-Sultan, injection of green tea displayed a significant inhibition of
50% of Namalwa tumors and RAP1-EIO and HS-Sultan tumor(27) through paralyzed tumor invasive activities.

In compared to chemotherapy drug cyclophosphamide, green tea exhibited anti-angiogenic effect in induction of.frequency of apoptotic endothelial and tumor cell and promoted tumor shrinking(27) by blocking the formation of new blood vessels in providing nutrients and fluid for tumor expansion.

10. Endometrial Cancer
In the experiment of green tea bioactive compound against progression of tumor xenografts of human endometrial cancer, (-)-epigallocatechin-3-gallate EGCG demonstrated a significant effect in reduced risk of endometrial cancer development(28) through the bioactive chemicals anti tumor angiogenesis properties.

The anti cancer active compound efficacy was attributed to the modulation of expression of vascular endothelial growth factor A (VEGFA) protein(28) in the established new vessel to stimulate the onset of cancer and cancer cell proliferation and HIF-1 functions(28) in activated transcription of many genes, in regulated cellular and systemic homeostatic response to external changes to tumor growth.

Application of EGCG also suppressed responses of chemokine (C-X-C motif) ligand 12 (CXCL12)(28) in expression of multiple physiological processes, in promoted invasion and metastasis of tumor cells in connected tissues of the uterine mucosa(28) (endometrium), thus reducing the infiltration of VEGFA-expressing tumor-associated macrophages (TAMs)(28) in supplying rapidly growing malignant tissues with essential nutrients and oxygen.

Further analysis also insisted that EGCG restricted secretion of vascular endothelial growth factor A (VEGFA) in initiated endometrial cancer growth by inhibiting the function of PI3K/AKT/mTOR/HIF1α pathway(29) in regulated many cellular processes, including cell survival, proliferation, and growth.

After taking account of all findings, treatment with EGCG reduced risk of endometrial cancer onset may be results of EGCG suppressed secretion in both fronts including decreased cancer cell-secreted VEGFA(29) but inhibited TAM-secreted VEGFA(29) in endometrial cancer progression.

Green tea polyphenol (-)-epigallocatechin-3-gallate reduced cancer expansion in suppressing the expression of proliferation markers, by acting indirectly to stimulate endometrial epithelial proliferation in estrogen receptor α, progesterone receptor, proliferating cell nuclear antigen and cyclin D1(29).

The overexpression of cyclin D1 has been linked to the development and progression of cancer.

Proliferating cell nuclear antigen is a protein with function in cell cycle regulation and/or DNA replication and important for both DNA synthesis and DNA repair.

The inhibition of EGCG also decreased the activation of ERK, the extracellular signal–regulated kinases protein(29) in cancer cell division and down expression of transcription factors fos and jun(29), the cellular immediate-early genes in induced transient cancer cell division and differentiation processes.

The function of EGCG in reduced risk of endometrial cancer also expressed through Bcl-2-associated X protein(29), cleavage of caspase-3 and poly(ADP-ribose) polymerase actions(29) in induction of cancer cell apoptosis and suppression of antiapoptotic protein Bcl-2 (B-cell lymphoma 2).

Bcl-2-associated X is a protein with function of anti- or pro-apoptotic regulators involved in a wide variety of cellular activities.

B-cell lymphoma 2, a family protein with function in regulation of cell apoptosis.

Cleavage of caspase-3 also is known as a critical executioner of apoptosis,

Poly(ADP-ribose) polymerase is a protein with function involved in a number of cellular processes, including programmed cell death.

Implicitly, application of EGCG also increased production of free radical expression in initiated the cytoxicity effect by reduced levels of antioxidant glutathione levels and activated the p38(29) in cancer cells death without inducing toxicity to normal cells

P38 mitogen-activated protein kinases (MAPKs) are activated by a wide range of cellular stresses as well as in response to inflammatory cytokines involved in cell differentiation, apoptosis and autophagy.

According to a systematic review of literature published on database of PubMed, Embase, Cochrane Library and China Biological Medicine Database upto February 2, 2015, green tea consumption was associated with a reduced risk of EC with a relative risk of .78 and each additional cup of green tea consumed per day decreased risk of developing EC by 11%(30).

Particularly, intake of green tea associated to attenuated risk of endometrial cancer was 84.33% in compared to 5.07 % of black tea(30).

11. Esophageal Cancer
According to statistic, 2,300 Canadians will be diagnosed with esophageal cancer in 2017.

In esophageal cancer cell lines Eca109 and Ec9706, injection of green tea EGCG plus chemodrug adriamycin (ADM) after 24 hours displayed a significantly increased cellular apoptosis(31).

According to flow cytometry assay, the application induced the elevation of ROS and ADM concentration in production of toxicity(31) to counter the reaction of tumor cell in diminished expression of mitochondrial membrane potential and ABCG2 protein to induce apoptosis(31).without harming to healthy cells.

ABCG2 protein expression plays a major role in multi-drug resistance, produced by tumor cells to accounter reaction to chemo-medicine.

Mitochondrial membrane potential is a central intermediate in oxidative energy metabolism, the deceased levels caused by toxicity ROS may result in energy deletion and subsequently, causing cells death.

 EGCG also inhibited the growth of Eca109 and Ec9706 cells through ameliorated the anti apoptotic bcl-2 protein expression(31) and promoted bax(31) and caspase-3 protein expressions(31) with functions in induced apoptosis in a dose- and time- dependent manner.

BCL2 family members form hetero- or homodimers and plays an important anti-apoptotic protein.

Caspase-3 protein.plays a central role in the execution-phase of cell apoptosis.

BAX gene, is a member of the Bcl-2 gene family plays an important role in mediation of cell death by apoptosis.

Compared to ADM treatment alone, the Eca109/ABCG2 multi-drug resistance cancer cells, rate of apoptosis and ADM concentration were significant higher in mitochondrial membrane potential in compared to ABCG2 expression(32).

In other word, injection of green tea plus ADM was more effective in induced cells death in Eca109/ABCG2 multi-drug resistance cancer cells with expression ROS and ADM in enhanced elevation cytotoxity activity in compared to ADM treatment alone.

After taking into account of others confounders, Dr, Liu L the lead author (32)said, " EGCG inhibited cell growth and induced esophageal cancer cell apoptosis. It reduced the bcl-2 protein expression and increased the bax and caspase-3 protein expression. EGCG reversed multi-drug resistance by reducing ABCG2 expression and increasing the anticancer drug concentration in cancer cells".

In esophageal squamous cell carcinoma, application of Epigallocatechin-3-gallate (EGCG) without ADM measured by flow cytometry assay, after 24 hours also inhibited cancer site proliferation by increased expression of ROS(33) to attenuate mitochondrial membrane potential function in energy metabolism and caspase-3 protein(33) to cause malignant cellular apoptosis, in a dose-and time-dependent manner.

PCR-TRAP argentation analysis during the experiment, EGCG also demonstrated a strong inhibition of the viability of Eca109 and Ec9706 cells(33) by suppressing cancer cell in alternated DNA transcript through telomerase activity.

The continuation of study of epigallocatechin-3-gallate (EGCG) on the human esophageal cancer cell line ECa109 also discover that EGCG demonstrated a decrease of cancer cell viability but a substantial rate of apoptosis was caused by increased expression of p16 gene demethylation in induced cancer cell cycle arrest and apoptosis through level p16 mRNA expression in suppressed tumor progression of invasive and aggressive behavior(33).and p16 protein expression in promoted tumor suppressible activity, in a dose- and time-dependent manner.

P16 gene demethylation plays an important role in cell cycle arrest and apoptosis. gene alternation was found in several types of cancer.

Low level of p16 mRNA expression is associated to progression of cancer with malignant and aggressive behavior.

Abnormalities of p16 gene and loss of p16 protein expression may be related to the pathogenesis and development of some cancers.

12. Bladder Cancer
According to statistic provided by cancer.net, 90% of people with bladder cancer are older than 55, and the average age of people diagnosed with bladder cancer is 73

In T24 human bladder cancer cell line, application of the chemopreventive/antiproliferative potential of (-)-epigallocatechin gallate (EGCG, the major phytochemical in green tea) induced anti malignant cell proliferation by modulating the expression of phosphatidylinositol 3' kinase/Akt in activated Bcl-2 family proteins(34)with function in regulation of cell death, thus enhancing apoptosis of T24 bladder cancer cell line in dose- and time-dependent manner.

The phosphatidylinositol 3'-kinase/AKT pathway is a crucial regulator of cellular processes including cell proliferation and apoptosis.

Bcl-2 family proteins is a modulator responsible for regulation of cell apoptosis.

In C3H/HeN mice subcutaneously implanted with MBT-2 murine bladder tumor cells, administration of EGCGs physically attached onto the surface of nanogold particles pNG(EGCG-adsorbed pNG) exerted a significant anti cancer proliferation through induction of apoptosis(35).

This action of anti cancer effect was attributed to mechanism of EGCG-pNG in activation of caspases which play an important role in induced cell apoptosis and inflammation through Bcl-family proteins(35) with function in control apoptosis by activating caspase proteases in the governing the space between outer and inner mitochondrial membrane.

Under stress, the mitochondrial pathway or the intrinsic pathway is activated depending to the release of proteins from the intermembrane space of mitochondria.

Caspase cascade, a family protease enzymes with function in programmed cell death and inflammation.

Injecting EGCG-pNG directly into the tumor site inhibited tumor expansion also ameliorated the function of vascular endothelial growth factor (VEGF)(35) in stimulated formation of new blood vessel in provided nutrients and oxygen for survival of cancer site in compared to
oral administration of EGCG in stimulated immune function in suppression of cancer progression.

Vascular endothelial growth factor, is a signal protein produced by cells in stimulated formation of blood vessel for cell division and site proliferation.

Based on information collected,, the prepared EGCG-pNG was more effective than free EGCG in inhibiting bladder tumor in model mice.

In bladder tumor induced by N-butyl-(-4-hydroxybutyl) nitrosaminre (BBN) 0.05% solution on 8 week-old female C3H/He mice for 14 or 24 weeks on treatment with or without green tea polyphenols (GTP) expressed a significant lower rate of tumor invasive frequency of 23.8%(36) in group treated with both GTP and BBN in compared to 65.2% in group treated with BBN alone(36).

The tumorvolume and microvascular density (MVD) as an independent predictor within a tumor.and the connective, functionally supportive framework of a biological cell, tissue, or organ region in the BBN+GTP group were also significantly lower than in BBN treated mice.

Green tea polyphenols inhibited tumor growth and invasion in mice with established bladder cancer through regulation of angiogenetic effect(36) in suppressed the forming of new blood vessel for the tumor cells proliferation, metastatic spread, as well as providing oxygen and nutrients and removal of waste products of cancer cells without exhibiting anti-carcinogenic effect.

13. Pancreatic Cancer
According to statistic, the average lifetime risk of pancreatic cancer for both men and women is about 1 in 65.

In human pancreatic ductal adenocarcinoma (PDAC) cell lines PancTu-I, Panc1, Panc89 and BxPC3, to compare the inhibited effect of EGCG to 2 components of catechins, namely, catechin gallate (CG) and epicatechin gallate (ECG), application of green tea 2 catechins components demonstrated a strong effect in inhibited proliferation(37) of PDAC cells in a dose- and time-dependent manner.

In comparison test, green tea CG and ECG exerted much stronger anti-proliferation effects than those of EGCG(37).

The proliferation of PancTu-I cells retained by green tea catechin was attributed to the antioxidant effect in interference of the cancer cell division cycle through mediating the cytokines in modulation of cell cycle regulatory proteins, such as cyclins(37), a cell division regulators, cyclin-dependent kinase (Cdk) enzymes(37) activated by cyclins(37) in regulated cell progression through cell cycle arrest, and CDK inhibitors(37) with function in prevented over proliferation of cancer cells.

All 3 components of green tea catechins also demonstrated a substantiated effect in ameliorated secretion of pro-inflammatory and invasion promoting proteins of the cancer cell through expression of TNF tumor necrosis factor(37) in activated of the nuclear factor NF-κB protein signalling(37) involved mediation of DNA transcript, pro inflammatory cytokines production and cancer cell survival.

Tumor necrosis factor is a cell signaling protein possessed a wide range of proinflammatory actions

NF-κB is a protein with function in controlled transcription of DNA, cytokine production and cell survival.

Once again, green tea catechins ECG and CG exhibit potent and much stronger anti-proliferate and anti-inflammatory activities on PDAC cells(37) in compared to EGCG

In human pancreatic cancer cells lines MIA PaCa-2 cells, injection of green tea EGCG plus Bleomycin, (BLM), an anti-cancer chemotherapeutic drug displayed a substantial effect in inhibited cell proliferation through cell cycle transition phase arrest and mitochondrial depolarization by mitochondrial permeability transition in induction of cell apoptosis, after 72 hours(38).

 EGCG and BLM exhibited anti-proliferative effects significantly in induced apoptosis of MIA PaCa-2 cells(38) and suggested that this combination could represent a new strategy with potential advantages for treatment of pancreatic cancer.

In pancreatic cancer cell lines MIA PaCa-2 and PANC-1, injection of pterostilbene isolated from blue berry and EGCG expressed a strongly additive antiproliferative effect after 72 hours with MIA(39) underwent S-phase arrest but not in cancer cell line PANC-1(39).

Both pterostilbene and EGCG induced mitochondrial depolarization in enhanced cytochrome c released from mitochondria(39) to trigger programmed cell death during the early stages of apoptosis was observed also in MIA, but not in PANC

EGCG increased caspase-3/7 function in induced cell apoptosis in MIA(39) but the combined treatment did not significantly increase the activity in either cell lines.(39) these contradictory activities may indicate that cell death occurs in MIA, possibly through another mechanism.

14. Kidney Cancer
According to statistic, kidney cancer is very uncommon in people younger than age 45 and among the 10 most common cancers in both gender.

In 250 newly diagnosed, histo-logically confirmed Clear cell renal cell carcinoma (CCRCC) cases and 299 sex-, age-matched healthy controls provided complete information by face-to-face interview in Shanghai between 2007 and 2009, application of green tea at dose of ≥500 ml/d demonstrated a significantly inverse association to risk of CCRCC(40).

Green tea consumption of lower than the said volume such as 8 oz (237 ml) or more cups/day was also associated to decrease renal cell cancer risk, in compared to non drinkers, according to the report of Brigham and Women's Hospital and Harvard Medical School.

CCRCC risk induced by interaction with the environmental exposures association to polymorphisms of the xenobiotic-metabolizing enzymes also inhibited by green tea extract through increasing serum and liver antioxidant capacity and strengthening stability of microsomal and lysosomal membranes of healthy cells in compared to control(41).

In free radical aspect, the examine Wistar rats induced renal cancer pre-treated with N-ethyl-N-hydroxyethylnitrosamine (EHEN) by oral injection of drinking water for 2 weeks, also found that administration of green tea extract catechin ( 0.1% polyphenon-60) over 30 weeks of period of treatment exhibits a significant effect in decreased the incidence of renal cell tumors greater than 3 mm in diameter(42) but not tumors that are less than 3 mm in diameter942), through over expression of antioxidant in suppression of reactive oxygen species (ROS) induced by N-ethyl-N-hydroxyethylnitrosamine (EHEN) pre-treatment(42).

In alternated gene expression increased prevalence of cancer in human subjects, application of green tea polyphenol, catechins  reverse change of DNA methylation in contributed to the tumor repressive gene of RGS2 (regulator of G-protein signaling 2) in modulated expression of cancers and increased the regulation of conversion of DNA to RNA (transcription) of these genes(43) in ameliorated risk of renal and other cancer(s).

Combined application of of green tea extract bioactive catechins and epigallocatechin gallate also showed to modulate DNA methylation by attenuating the effect of DNA methyltransferase 1 (DNMT1)(43) to ensure the fidelity of replication of inherited epigenetic patterns.

Aberrant DNA methylation patterns are associated with increased prevalence of renal and other tumor(s).

15. Skin Cancer
According to statistic, approximately, 87,110 new cases of invasive melanoma are diagnosed in the U.S every years

The evaluation of green tea effect in overexposure to environmental solar ultraviolet (UV) radiation (290-400 nm) which has been found to increase risk of the development of melanoma and non-melanoma skin cancers in mice model showed that oral administration of green tea pylophenols (GTPs) in drinking water or the topical application of EGCG prevents UVB-induced skin tumor development in tested subjects(44).

 (-)-Epigallocatechin-3-gallate (EGCG), the major and most photoprotective polyphenolic component of green tea exhibited a protective activity against UV in induction of skin cancer(44), through induction of immunoregulatory cytokine interleukin (IL) 12 in differentiation of naive T cells into Th1 cells(44) and acted as T cell-stimulating factor in stimulate the growth and function of T cells.

Moreover, interleukin (IL) 12 also demonstrated a significant effect as an antagonist against immunosuppression induced by solar/ultraviolet (UV) radiation(44) by restoring immune responses and also stimulating DNA repair.

Green tea (-)-Epigallocatechin-3-gallate (EGCG) inhibited UV in induction of skin tumors; angiogenetic effect(45)in stimulated production of new blood vessels to provide nutrients and oxygen for cancer cells proliferation and survivals and initiated cytotoxic T lymphocyte cells in induced cancer and infectious and damage cells apoptosis.

Additional study of green tea polyphenols (GTPs) in prevention of UVB irradiated (80 mJ/cm(2)) 3 times each week for 24 wk in induced skin cancer in mice divided in to group consumed water and group fed with water containing 2 g/L GTPs, showed that group treated with GTPs displayed a significant reduced UVB-induced tumor incidence by 35%, tumor multiplicity by 63%, and tumor growth by 55% in compared to non treatment group(46).

Group treated with GTPs+UVB also demonstrated a reduced expression of the matrix metalloproteinases (MMP)-2 and MMP-9(46), which are activators associated with progression from benign to advanced cancer and expression of specific endogenous tissue inhibitors of metalloproteinases (TIMPs), tissues inhibitor of MMP in skin tumors in compared to mice treated with UVB alone.

 GTPs+UVB group also reduced expressions of CD31 and vascular endothelial growth factor(46), in activated development of new blood vessel to nourish skin tumor cells proliferation and site expansion and inhibited expression of proliferating cell nuclear antigen, a key factor in DNA replication and cell cycle regulation in skin cancer in compared to UVB group.

Mice treated with GTPs+UVB group also showed more cytotoxic CD8(+) T cells in the tumors in compared to UVB group(46) by exhibited greater activation of caspase-3 epression in induced apoptosis of the tumor cells.

16. Oral Cancer
According to statistic, 1 in 75 men and 1 in 150 women will be diagnosed with oral cancer during their lifetime.

In human oral squamous carcinoma cells (SCC-25, SCC-9), application of green tea catechin, (-)-epigallocatechin-3-gallate (EGCG) suppressed SIRT3 mRNA(47) and protein expression in induction of SCC-25 cells proliferation(47), through antioxidant effect in attenuated function of SIRT3 in contribution to cancer cell survival via mRNA transmitting by modulating oxidative stress..

Some reserachers also insisted that SIRT 3 may be considered as a bio-maker for targeting stage and grade of cancer progression.

Green tea bioactive EGCG also up regulated the nuclear localization of the estrogen-related receptor α (ERRα)(47) in inhibited oral cell carcinoma tumors by regulating SIRT3(47) in expression of cancer cellular metabolism.

EGCG application displayed a significant effect in modulated the mRNA expressions of SIRT3-associated to cancer cell in induction of cell proliferation through inhibiting the production of reactive oxidative species in precipitated chain reactive in initiation of cancer cell division.

In ROS perspective, oral administration of green tea EGCG by targeting the protein SIRT3(48) in exhibited antioxidant effect in protect healthy cells without affecting formation of ROS to facilitate oral cancer cell apoptosis through cytotoxicity(48).

Dr. Tao L(48), after taking into account of other cofounders, said, "SIRT3 represents a novel potential target through which EGCG exerts differential prooxidant effects in cancer and normal cells".

EGCG treatment increased the production of mitochondrial H2O2 in SCC-25 cells(48) within 6 hours before inducing cancer cells apoptosis.

In antioxidant activity. green extract EGCG induced differential expression of genes related to antioxidant defense in oral cancer cell and gingival fibroblasts(48), which are critical in sustaining inflammation in periodontal disease through ameliorated expression of metallothionein 3 in induction of degeneration of cells and superoxide dismutase 2/3, and thioredoxin reductase 2(48) in facilitate oxidative stress to induce oncogenesis without increased cell proliferation of human gingival fibroblast -1 (HGF-1)(48).

Additional examination indicated that the application also exhibited anti oral cancer apoptosis by increased expression of mitochondrial ROS(48) and mitochondrial dysfunction(48) in facilitated intoxicate effect without causing harm to the gingival fibroblasts through antioxidant selective activities.

Green tea with promising chemo properties due to their decreased dose and limited toxicity profiles, Dr. Ramshankar V(49), the lead author said, "It is worthwhile to include green tea extract in an oral screening program for evaluating the pre-malignant lesions comparing the results between the treated and untreated group. Given the wide acceptance of green tea, its benefits may help in effective chemo-prevention oral cancer".

Summary
Taken together, the information findings suggested that green tea and its bioactive polyphenols such as  catechin, (-)-epigallocatechin-3-gallate (EGCG) may have a profound and therapeutic effect in reduced risk of various types of cancer, however, due to limitation of this review, further research and studies are necessary before green tea can be recommended as a functional food in prevented risk and adjunct therapy for treatment of cancers.

Author Biography
Kyle J. Norton (All right reserved)
Health article writer and researcher; Over 10.000 articles and research papers have been written and published on line, including world wide health, ezine articles, article base, healthblogs, selfgrowth, best before it's news, the karate GB daily, etc.,.
Named TOP 50 MEDICAL ESSAYS FOR ARTISTS & AUTHORS TO READ by Disilgold.com Named 50 of the best health Tweeters Canada - Huffington Post
Nominated for shorty award over last 4 years
Some articles have been used as references in medical research, such as international journal Pharma and Bio science, ISSN 0975-6299.

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