Abstract
This review article focuses on (-)-epigallocatechin-3-gallate (EGCG) as a therapeutic agent for chemoprevention and cancer treatment. EGCG has been supported by epidemiological evidence as a chemopreventive agent. Although preclinical studies have demonstrated its chemosensitizing effects in conjunction with chemotherapy, several studies have reported antagonistic interactions. Due to the lack of clinical research, further evidence is required to better understand the effectiveness of EGCG in cancer therapy.
- Introduction
Cancer is a growing concern in Canada; it has been estimated that 2 in 5 Canadians are expected to develop cancer, of which 1 in 4 will die (Canadian Cancer Society 2014). Chemotherapy is a form of cancer treatment (National Cancer Institute 2014), but a key issue is overcoming chemoresistance of cancer cells (Farrell 2011). To address this issue, a variety of agents are worth considering as an adjunctive treatment with chemotherapy.
Green tea, derived from the Camellia sinensis plant, is concentrated in catechins, with (-)-epigallocatechin-3-gallate (EGCG) being the most abundant (Du 2012). Accumulating epidemiological evidence has demonstrated EGCG’s potential in chemoprevention (Lecumberri 2013). Preclinical studies have supported the role of EGCG as an adjunctive treatment for various cancer types; EGCG has shown chemosensitization by increasing tumor cell susceptibility to chemotherapy drugs (Lecumberri 2013, National Cancer Institute 2015). While some studies presented positive results, there is a lack of confirmatory studies regarding biochemical interactions between EGCG and chemotherapy agents (Lecumberri 2013). Therefore, the objective of this article is to evaluate the effect of EGCG as a chemopreventive agent as well as an adjunctive chemotherapeutic agent.
- Chemoprevention
There are three stages of chemoprevention: primary, secondary, and tertiary.
2.1 Primary Prevention
Primary prevention focuses on preventing malignancies in healthy individuals (Millar 2011). Research in East Asia, consisting of case-control and cohort studies, has shown varied associations between green tea consumption and cancer development. Green tea consumption was correlated with a decreased risk of esophageal squamous cell carcinoma, multiple myeloma, and advanced prostate cancer (Chen 2009, Kurahashi 2007, Wang 2012). However, a positive association was found in head and neck cancer, where green tea consumption appeared to increase the risk of cancer (Oze 2014). No significant association was found in localized prostate and pancreatic cancers (Kurahashi 2007, Lin 2008). Moreover, inconsistencies were found regarding the association between green tea consumption and the risk of breast cancer, as one study demonstrated a decreased risk while another discovered no association (Iwasaki 2013, Shrubsole 2008).
2.2 Secondary Prevention
Secondary prevention involves slowing down precancerous lesions from progressing into cancers (Millar 2011). In a randomized control trial on high-grade prostate intraepithelial neoplasia, participants were given either 600 mg of EGCG or placebo for one year to reduce their chances of developing prostate cancer. Results showed a 3% incidence in the intervention group compared to 30% in the placebo group (Bettuzzi 2006). Moreover, another study assessed the potential for green tea extract (GTE) in preventing metachronous colorectal adenoma. The study found that 1.5 g of GTE supplementation for one year reduced the incidence and size of relapsed adenomas (Shimizu 2008).
2.3 Tertiary Prevention
Tertiary prevention involves preventing new cancers from developing in individuals who are in remission (Millar 2011). A phase II trial assessed the role of EGCG as a maintenance therapy in 16 women with a history of advanced stage ovarian cancer. They received 500 mL of green tea, containing 640 mg/L of EGCG. To continue the trial, 50% of participants must be free of recurrence at the 18-month follow-up. However, this threshold was not met since only 5 out of the 16 patients were cancer-free, suggesting that EGCG is not a promising agent for maintenance therapy in this population (Trudel 2013).
- Biochemical Interactions of EGCG
3.1 Redox Activity
EGCG has both antioxidant and pro-oxidant properties (Lambert 2010). As an antioxidant, it neutralizes free radical species produced by carcinogenic cells. As a pro-oxidant, EGCG induces oxidative stress in malignant cells (Lambert 2010). When EGCG was introduced in esophageal squamous cell lines, there was an increased concentration of intracellular reactive oxygen species (ROS), which stimulated the release of pro-apoptotic factors against cancer cells (Hou 2006). Moreover, EGCG’s pro-oxidative properties work in complementary mechanisms to chemotherapy. Specifically, in human promyelocytic leukemia cell lines, EGCG acts synergistically with arsenic trioxide through the Fenton reaction to generate ROS (Lee 2011). In human colon, bladder, and gastric cancer cell lines, EGCG-induced ROS increased the bioavailability of 5-fluorouracil (5-FU) (Qiao 2011). In ovarian cancer cell lines, EGCG exhibited chemosensitizing effects and increased cisplatin’s potency by reducing the activity of glutathione, an antioxidant that hinders the effectiveness of cisplatin (Chan 2006).
3.2 Induction of Cell Cycle Arrest
EGCG promotes cell cycle arrest by inhibiting cancer cell growth through the modulation of cyclin-dependent kinases (Baek 2004, Masuda 2001). Specifically, EGCG reduces the expression of cyclin D1, a protein that facilitates cell cycle progression and is overexpressed in human cancers such as breast, ovarian and esophageal cancers (Courjal 1996, Gillett 1994, Inomata 1998, Jirawatnotai 2011, Khan 2006). In human head and neck squamous cell carcinoma, EGCG treatment reduced phosphorylated retinoblastoma and induced p21Cip1 and p27Kip1 expression, resulting in cell cycle arrest at the G1 phase (Masuda 2001). Moreover, in prostate cancer cells, EGCG increased the expression of p16, p18 and p53, negative regulators of G1 progression (Singh 2011).
3.3 Inhibition of Telomerase Activity
EGCG inhibits telomerase activity, which is overexpressed in cancer cells, by stimulating telomere fragmentation (Kim 1994, Singh 2011). The concurrent administration of EGCG with cisplatin or tamoxifen in human glioma cell lines, showed significant chemosensitizing effects through telomerase inhibition (Shervington 2008). This study, along with another preclinical study in breast cancer cell lines, EGCG significantly reduced the mRNA expression of human telomerase reverse transcriptase, the main regulatory subunit of telomerase, resulting in significant shortening of telomeres. The subsequent genomic instability induced apoptosis in these cancer cells (Berletch 2008, Shervington 2008). Similar results have also been shown in human small-cell lung carcinoma (Sadava 2007).
3.4 Apoptosis
EGCG, in conjunction with chemotherapy agents, upregulates apoptosis. In human prostate cancer cells, EGCG combined with taxane resulted in an overexpression of pro-apoptotic proteins, such as p53. The overexpression of p53 increased the chemosensitivity of cancer cells to the taxane treatment (Stearns 2011). Moreover, in urothelial carcinoma cells, EGCG enhanced the cytotoxicity of celecoxib by downregulating glucose-regulated protein 78, which has anti-apoptotic properties (Li 2006, Huang 2012). Furthermore, EGCG downregulates anti-apoptotic protein Bcl-2 and upregulates pro-apoptotic protein Bax, increasing the Bax:Bcl-2 ratio (Kwak 2013, Lang 2009, Nihal 2010, Tang 2012).
3.5 Reduction of Angiogenesis
EGCG has shown to reduce angiogenesis, a process essential for tumour growth and metastasis (Jung 2001). In human colorectal cancer cells, EGCG decreased vascular endothelial growth factor (VEGF) mRNA levels and VEGF receptor-2 levels; it also inhibited cell survival-associated PI3K/Akt and MAPK/ERK signaling pathways (Shimizu 2010). In mouse models involving breast and prostate cancers, EGCG inhibited the expression of VEGF-related factors, HIF-1α and NFκB (Gu 2013, Henning 2012, Shimizu 2010). In Kaposi’s sarcoma, EGCG inhibited the activity of angiogenic enzymes, matrix metalloproteinase 2 and 9 (Fassina 2004).
Moreover, EGCG-mediated VEGF inhibition was also seen when combined with vorinostat in cholangiocarcinoma cell lines (Kwak 2013). In human gastric cancer xenografts in mice, EGCG enhanced the anti-angiogenic activity of capecitabine and docetaxel (Wu 2012a, Wu 2012b). Co-administration of EGCG with cisplatin also demonstrated similar effects in mice with non-small cell lung carcinoma (NSCLC) (Deng 2013).
3.6 Alternation of Drug Pharmacokinetics
Adjuvant treatment of EGCG with chemotherapy can increase intracellular drug concentrations, thereby blocking tumor growth (Liang 2010). EGCG increased the plasma concentration of 5-FU in healthy rats by decreasing 5-FU catabolism (Qiao 2011). In vitro and in vivo studies of prostate cancer revealed that EGCG enhanced doxorubicin (DOX) retention in malignant cells, thereby increasing DOX-dependent cell death and chemosensitivity to DOX (Stearns 2010).
3.7 Reversal of Chemoresistance Through Proteins and Genes
EGCG can overcome drug resistance by modulating proteins and genes that induce chemoresistance in cancer cells. For instance, in tamoxifen-resistant breast carcinoma cell lines, EGCG treatment inhibited the activity of the breast cancer resistance protein, which facilitated the chemosensitization of cancer cells to tamoxifen (Farabegoli 2010). Moreover, in NSCLC, EGCG chemosensitized cancer cells to cisplatin by significantly reversing the hypermethylated status of candidate genes (Zhang 2015). EGCG has also been shown chemosensitize NSCLC cells to cisplatin by inhibiting the expression of a MAPK-associated microRNA, hsa-miR-98–5p (Zhou 2014).
3.8 Antagonistic Interactions
EGCG interacts antagonistically with certain classes of chemotherapy drugs. For example, EGCG decreases the activity of boronic acid-based proteasome inhibitors, such as bortezomib, MG-262, and PS-IX, by binding with boronic acids (Golden 2009, Bannerman 2011). In multiple myeloma and glioblastoma cell lines, EGCG at a dose of 20 μM counteracted the cytotoxic activity of bortezomib, preventing downstream events including endoplasmic reticulum stress and apoptosis (Golden 2009, Bannerman 2011). However, in xenograft mouse models of human multiple myeloma, antagonism between EGCG and bortezomib only occurred when plasma concentrations of EGCG were above 200 μM (Bannerman 2011). Another instance of an antagonistic interaction was when EGCG was used in conjunction with sunitinib, a receptor protein-tyrosine kinase inhibitor. In murine stomachs, EGCG-sunitinib binding formed sticky semi-solid contents, which lowered plasma concentrations of sunitinib (Ge 2011).
- Clinical Trials on EGCG
Phase I and II clinical trials have examined the maximum tolerated dose (MTD) of EGCG. A phase I RCT involving women with a history of breast cancer used Polyphenon E, a green tea catechin mixture, containing 200 mg of EGCG. This study defined the MTD as 600 mg of EGCG twice daily to avoid long-term toxicity effects, such as indigestion, weight gain, insomnia, and rectal bleeding (Crew 2012). In another phase I trial, advanced lung cancer patients received a daily oral dose of GTE using a dose-escalation method, starting at 0.5 g/m2. The MTD of GTE was 3 g/m2 to avoid dose-limiting toxicities including diarrhea, nausea and hypertension. However, no objective tumor responses were noted, suggesting that GTE alone has limited cytotoxic activity (Laurie 2005).
In a phase I study of stage III NSCLC patients receiving concurrent chemoradiotherapy, EGCG was administered at doses ranging from 40 to 440 µmol/L. A rapid regression in acute radiation-induced esophagitis (ARIE) and reduction in pain score was observed. MTD was not defined as no grade III/IV toxicities resulted, and EGCG was deemed a safe and feasible treatment (Zhao 2014). In a follow-up phase II trial, lung cancer patients received 440 µmol/L of EGCG concurrently with chemoradiotherapy or radiotherapy alone. EGCG was shown to be an effective method to deal with ARIE, suggesting its potential role as a radioprotective agent (Zhao 2015).
In a phase II trial, 2000 mg of EGCG twice daily was well tolerated in chronic lymphocytic leukemia (CLL) patients. It was also demonstrated that EGCG reduced absolute lymphocyte count and lymphadenopathy (Shanafelt 2012). In another phase II trial, prostate cancer patients received a daily dosage of 800 mg of EGCG, in a Polyphenon E capsule. EGCG was administered before their radical prostatectomy, for a medium dosing period of 34.5 days. There was a significant reduction in a variety of serum markers such as prostate specific antigen, hepatocyte growth factor, insulin-like growth factor 1, and VEGF (McLarty 2009). This demonstrates EGCG’s potential in regulating cancer markers that indicate disease status in certain cancers.
One clinical trial used a botanical preparation, MB-6, which included GTE along with fermented soybean extract and curcumin, in colorectal cancer patients receiving chemotherapy. The placebo group did not differ in best overall response rate and survival when compared to the MB-6 treated group. However, the MB-6 treated group had a significantly slower disease progression rate, while the placebo group had significantly higher incidence of adverse events of at least grade IV (Chen 2014). Based on the evidence presented, the positive outcomes that resulted can be partly attributed to EGCG’s potential as a chemosensitizing agent.
- Bioavailability
EGCG has a limited bioavailability with a half-life of 3.4 ± 0.3 hours. In a study examining the maximum plasma concentration of tea catechins, healthy individuals received an oral dose of EGCG (2 mg/kg) in the morning after overnight fasting. The highest plasma concentration of EGCG was seen (77.9 +/- 22.2 ng/mL) 1-2 hours post-administration (Lee 2002). EGCG absorption occurs mostly in the small intestine. Colonic microflora in the large intestine breaks EGCG down to phenolic acids (Auger 2008, Stalmach 2009, Roowi 2010). Various substances can affect the oral bioavailability of EGCG. For example, casein proteins in milk, was hypothesized to form complexes with tea catechins (Lorenz 2007). In addition, sucrose and ascorbic acid may improve catechin bioavailability by enhancing intestinal uptake from tea (Peters 2010). Furthermore, piperine in black pepper spice also increased EGCG bioavailability (Lambert 2004). Moreover, omega-3 polyunsaturated fatty acids in fish oil may enhance not only EGCG bioavailability but may also improve its efficacy by inhibiting tumor multiplicity (Bose 2007, Giunta 2010).
- Limitations
In the aforementioned studies, the main limitation in quantifying the chemopreventive effects of EGCG was the heterogeneity in study designs. The studies used varying sample size, eligibility criteria, length of follow-up, and guidelines surrounding the administration of EGCG. This may have affected results of the studies. For example, Shrubsole et al. showed that EGCG produced a statistically significant effect in preventing breast cancer, whereas another study by Iwasaki et al. did not show significant results.
Moreover, the majority of research studies have shown that EGCG can synergistically chemosensitize various types of cancer cells to chemotherapy. However, many of these studies are limited to in vitro and in vivo trials. Due to the lack of confirmatory studies, it is difficult to validate the synergistic effects of EGCG and chemotherapy as a combination therapy. Such studies must account for the different types of chemotherapy drugs, optimal EGCG dosage, the type and stage of cancer. This is reinforced by Chen et al. who described that EGCG as an adjunctive therapy is dependent upon cancer type and molecular pathway.
Although EGCG and chemotherapy agents show enhanced effectiveness against cancer cells, the literature on the biochemical interactions is still unclear. Further research examining these biochemical interactions is necessary to fully understand the possibility of antagonistic effects of EGCG on chemotherapy drugs.
Finally, there is a lack of clinical trials that investigate the use of EGCG as a supplement for cancer patients receiving chemotherapy. Such clinical studies can evaluate whether EGCG can be used in a cancer therapy to potentially enhance the effects of chemotherapy.
- Conclusion
Thus far, existing research on EGCG as a chemopreventive agent and adjunctive treatment to chemotherapy has shown potential. Despite some controversies surrounding EGCG’s antagonistic interactions with chemotherapy drugs, preclinical studies have demonstrated the effectiveness of EGCG in chemosensitization via various mechanisms including redox activity, inhibition of telomerase activity, cell cycle arrest, apoptosis, reduced angiogenesis, and synergistic pharmacokinetics. However, there were very few clinical trials looking at EGCG in conjunction with chemotherapy in cancer patients. Therefore, this lack of human trials highlights the need for further research in order to optimize cancer care.
References
Auger C, Mullen W, Hara Y, Crozier A. Bioavailability of polyphenon E flavan-3-ols in humans with an ileostomy. J Nutr. 2008;138:1535S–1542S.
Baek S. Epicatechin gallate-induced expression of NAG-1 is associated with growth inhibition and apoptosis in colon cancer cells. Carcinogenesis. 2004;25(12):2425-2432.
Bannerman B, Xu L, Jones M, Tsu C, Yu J, Hales P, Monbaliu J, Fleming P, Dick L, Manfredi M, Claiborne C, Bolen J, Kupperman E, Berger A. Preclinical evaluation of the antitumor activity of bortezomib in combination with vitamin C or with epigallocatechin gallate, a component of green tea. Cancer Chemotherapy and Pharmacology. 2011;68(5):1145-1154.
Berletch J, Liu C, Love W, Andrews L, Katiyar S, Tollefsbol T. Epigenetic and genetic mechanisms contribute to telomerase inhibition by EGCG. J Cell Biochem. 2008;103(2):509-519.
Bettuzzi S. Chemoprevention of Human Prostate Cancer by Oral Administration of Green Tea Catechins in Volunteers with High-Grade Prostate Intraepithelial Neoplasia: A Preliminary Report from a One-Year Proof-of-Principle Study. Cancer Research. 2006;66(2):1234-1240.
Bose M, Hao X, Ju J, Husain A, Park S, Lambert JD, Yang CS. Inhibition of tumorigenesis in ApcMin/+ mice by a combination of (−)-epigallocatechin-3-gallate and fish oil. J Agric Food Chem. 2007;55:7695–7700.
Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2014. Toronto, ON: Canadian Cancer Society; 2014.
Chan M, Soprano K, Weinstein K, Fong D. Epigallocatechin-3-gallate delivers hydrogen peroxide to induce death of ovarian cancer cells and enhances their cisplatin susceptibility. Journal of Cellular Physiology. 2006; 207(2):389-396.
Chen W, Yang T, Chen H, Chen H, Chiang H, Lin T, Yeh C, Ke T, Chen J, Hsiao K, Kuo M. Effectiveness of a novel herbal agent MB-6 as a potential adjunct to 5-fluoracil–based chemotherapy in colorectal cancer. Nutrition Research. 2014;34(7):585-594.
Chen Y, Lee C, Wu I, Liu J, Wu D, Lee J, Goan Y, Chou S, Huang C, Lee C, Hung H, Yang J, Wu M. Food intake and the occurrence of squamous cell carcinoma in different sections of the esophagus in Taiwanese men. Nutrition. 2009;25(7-8):753-761.
Courjal F, Louason G, Speiser P, Katsaros D, Zeillinger R, Theillet C. Cyclin gene amplification and overexpression in breast and ovarian cancers: Evidence for the selection of cyclin D1 in breast andcyclin E in ovarian tumors. International Journal of Cancer. 1996;69(4):247-253.
Crew K, Brown P, Greenlee H, Bevers T, Arun B, Hudis C, McArthur H, Chang J, Rimawi M, Vornik L, Cornelison T, Wang A, Hibshoosh H, Ahmed A, Terry M, Santella R, Lippman S, Hershman D. Phase IB Randomized, Double-Blinded, Placebo-Controlled, Dose Escalation Study of Polyphenon E in Women with Hormone Receptor-Negative Breast Cancer. Cancer Prevention Research. 2012;5(9):1144-1154.
Deng P, Hu C, Xiong Z, Yang H, Li Y. Treatment with EGCG in NSCLC leads to decreasing interstitial fluid pressure and hypoxia to improve chemotherapy efficacy through rebalance of Ang-1 and Ang-2. Chinese Journal of Natural Medicines. 2013;11(3):245-253.
Du GJ, Zhang Z, Wen XD, et al. Epigallocatechin Gallate (EGCG) is the most effective cancer chemopreventive polyphenol in green tea. Nutrients. 2012;4(11):1679-91.
Farrell A. A close look at cancer. Nat Med. 2011;17(3):262-265.
Farabegoli F, Papi A, Bartolini G, Ostan R, Orlandi M. (-)-Epigallocatechin-3-gallate downregulates Pg-P and BCRP in a tamoxifen resistant MCF-7 cell line. Phytomedicine. 2010;17(5):356-362.
Fassina G. Mechanisms of Inhibition of Tumor Angiogenesis and Vascular Tumor Growth by Epigallocatechin-3-Gallate. Clinical Cancer Research. 2004;10(14):4865-4873.
Ge J, Tan B, Chen Y, Yang L, Peng X, Li H, Lin H, Zhao Y, Wei M, Cheng K, Li L, Dong H, Gao F, He J, Wu Y, Qiu M, Zhao Y, Su J, Hou J, Liu J. Interaction of green tea polyphenol epigallocatechin-3-gallate with sunitinib: potential risk of diminished sunitinib bioavailability. J Mol Med. 2011;89(6):595-602.
Gillett C, Fantl V, Smith R, Fisher C, Bartek J, Dickson C, Barnes D, Peters G. Amplification and overexpression of cyclin D1 in breast cancer detected by immunohistochemical staining. Cancer Res. 1994 Apr 1;54(7):1812-7.
Giunta B, Hou H, Zhu Y, Salemi J, Ruscin A, Shytle RD, Tan J. Fish oil enhances anti-amyloidogenic properties of green tea EGCG in Tg2576 mice. Neurosci Lett. 2010;471:134–138.
Golden E, Lam P, Kardosh A, Gaffney K, Cadenas E, Louie S, Petasis N, Chen T, Schonthal A. Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors. Blood. 2009;113(23):5927-5937.
Gu J, Makey K, Tucker K, Chinchar E, Mao X, Pei I, Thomas E, Miele L. EGCG, a major green tea catechin suppresses breast tumor angiogenesis and growth via inhibiting the activation of HIF-1α and NFκB, and VEGF expression. Vasc Cell. 2013;5(1):9.
Henning S, Wang P, Said J, Magyar C, Castor B, Doan N, Tosity C, Moro A, Gao K, Li L, Heber D. Polyphenols in brewed green tea inhibit prostate tumor xenograft growth by localizing to the tumor and decreasing oxidative stress and angiogenesis. The Journal of Nutritional Biochemistry. 2012;23(11):1537-1542.
Hou Z, Xiao H, Lambert J, You H, Yang CS. Green tea polyphenol, (−)-epigallocatechin-3-gallate, induces oxidative stress and DNA damage in cancer cell lines, xenograft tumors, and mouse liver. ProcAmer Assoc Cancer Res. 2006
Huang K, Kuo K, Chen S, Weng T, Chuang Y, Tsai Y, Pu Y, Chiang C, Liu S. Down-Regulation of Glucose-Regulated Protein (GRP) 78 Potentiates Cytotoxic Effect of Celecoxib in Human Urothelial Carcinoma Cells. PLoS ONE. 2012;7(3):e33615.
Inomata M, Uchino S, Tanimura H, Shiraishi N, Adachi Y, Kitano S. Amplification and overexpression of cyclin D1 in aggressive human esophageal cancer. Oncol Rep. 1998;.
Iwasaki M, Mizusawa J, Kasuga Y, Yokoyama S, Onuma H, Nishimura H, Kusama R, Tsugane S. Green Tea Consumption and Breast Cancer Risk in Japanese Women: A Case-Control Study. Nutrition and Cancer. 2013;66(1):57-67.
Jirawatnotai S, Hu Y, Michowski W, Elias J, Becks L, Bienvenu F, Zagozdzon A, Goswami T, Wang Y, Clark A, Kunkel T, van Harn T, Xia B, Correll M, Quackenbush J, Livingston D, Gygi S, Sicinski P. A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers. Nature. 2011;474(7350):230-234.
Jung Y, Ellis L. Inhibition of tumour invasion and angiogenesis by epigallocatechin gallate (EGCG), a major component of green tea. International Journal of Experimental Pathology. 2001;82(6):309-316.
Khan N, Afaq F, Saleem M, Ahmad N, Mukhtar H.Targeting multiple signaling pathways by green tea polyphenol -epigallocatechin-3-gallate. Cancer Res. 2006 Mar;66(5):2500-5.
Kim N, Piatyszek M, Prowse K, Harley C, West M, Ho P, Coviello G, Wright W, Weinrich S, Shay J. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994;266(5193):2011-2015.
Kurahashi N, Sasazuki S, Iwasaki M, Inoue M. Green Tea Consumption and Prostate Cancer Risk in Japanese Men: A Prospective Study. American Journal of Epidemiology. 2007;167(1):71-77.
Kwak T, Kim D, Chung C, Lee H, Kim C, Jeong Y, Kang D. Synergistic Anticancer Effects of Vorinostat and Epigallocatechin-3-Gallate against HuCC-T1 Human Cholangiocarcinoma Cells. Evidence-Based Complementary and Alternative Medicine. 2013;2013:1-11.
Lambert JD, Hong J, Kim DH, Mishin VM, Yang CS. Piperine enhances the bioavailability of the tea polyphenol (−)-epigallocatechin-3-gallate in mice. J Nutr. 2004;134:1948–1952.
Lambert J, Elias R. The antioxidant and pro-oxidant activities of green tea polyphenols: A role in cancer prevention. Archives of Biochemistry and Biophysics. 2010;501(1):65-72.
Lang M, Henson R, Braconi C, Patel T. Epigallocatechin-gallate modulates chemotherapy-induced apoptosis in human cholangiocarcinoma cells. Liver International. 2009;29(5):670-677.
Laurie SA, Miller VA, Grant SC, Kris MG, Ng KK. Phase I study of green tea extract in patients with advanced lung cancer. Cancer Chemother Pharmacol. 2005;55:33-38.
Lecumberri E, Dupertuis Y, Miralbell R, Pichard C. Green tea polyphenol epigallocatechin-3-gallate (EGCG) as adjuvant in cancer therapy. Clinical Nutrition. 2013;32(6):894-903.
Lee M, Maliakal P, Chen L, Meng X, Bondoc F, Prabhu S, Lambert G, Mohr S, Yang C. Pharmacokinetics of tea catechins after ingestion of green tea and (-)-epigallocatechin-3-gallate by humans: formation of different metabolites and individual variability. Cancer Epidemiology, Biomarkers & Prevention. 2002;11(10 Pt 1):1025-32.
Lee T, Cheng I, Shue J, Wang T. Cytotoxicity of arsenic trioxide is enhanced by Epigallocatechin-3-gallate via suppression of ferritin in cancer cells. Toxicology and Applied Pharmacology. 2011;250(1):69-77.
Li J, Lee A. Stress Induction of GRP78/BiP and Its Role in Cancer. CMM. 2006;6(1):45-54.
Liang. Green tea catechins augment the antitumor activity of doxorubicin in an in vivo mouse model for chemoresistant liver cancer. International Journal of Oncology. 2010;37(1).
Lin Y, Kikuchi S, Tamakoshi A, Yagyu K, Obata Y, Kurosawa M, Inaba Y, Kawamura T, Motohashi Y, Ishibashi T. Green Tea Consumption and the Risk of Pancreatic Cancer in Japanese Adults. Pancreas. 2008;37(1):25-30.
Lorenz M, Jochmann N, von Krosigk A, Martus P, Baumann G, Stangl K, Stangl V. Addition of milk prevents vascular protective effects of tea. Eur Heart J. 2007;28:219–223.
Masuda M, Suzui M, Weinstein IB. Effects of epigallocatechin-3-gallate on growth, epidermal growth factor receptor signaling pathways, gene expression, and chemosensitivity in human head and neck squamous cell carcinoma cell lines. Clin Cancer Res. 2001 Dec;7(12):4220-9.
McLarty J, Bigelow R, Smith M, Elmajian D, Ankem M, Cardelli J. Tea Polyphenols Decrease Serum Levels of Prostate-Specific Antigen, Hepatocyte Growth Factor, and Vascular Endothelial Growth Factor in Prostate Cancer Patients and Inhibit Production of Hepatocyte Growth Factor and Vascular Endothelial Growth Factor In vitro. Cancer Prevention Research. 2009;2(7):673-682.
Millar L. What Is Chemoprevention? | Oncolink – Cancer Resources [Internet]. Oncolink.org. 2011 [cited 2015 Mar 24]. Available from: http://www.oncolink.org/resources/article1.cfm?id=1049
National Cancer Institute. Chemotherapy and you: support for people who have cancer [Internet]. 2014 [cited 2015 Feb 23] Available at: http://www.cancer.gov/cancertopics/coping/chemotherapy-and-you.
National Cancer Institute. Definition of chemosensitizer – NCI Dictionary of Cancer Terms [Internet]. 2015 [cited 2015 Feb 23]. Available from: http://www.cancer.gov/dictionary?cdrid=45640
Nihal M, Roelke C, Wood G. Anti-Melanoma Effects of Vorinostat in Combination with Polyphenolic Antioxidant Epigallocatechin-3-Gallate (EGCG). Pharm Res. 2010;27(6):1103-1114.
Oze, Isao, Keitaro Matsuo, Daisuke Kawakita, Satoyo Hosono, Hidemi Ito, Miki Watanabe, Shunzo Hatooka et al. “Coffee and green tea consumption is associated with upper aerodigestive tract cancer in Japan.” International Journal of Cancer 135, no. 2 (2014): 391-400. http://www.ncbi.nlm.nih.gov/pubmed/24310779
Peters CM, Green RJ, Janle EM, Ferruzzi MG. Formulation with ascorbic acid and sucrose modulates catechin bioavailability from green tea. Food Res Int. 2010;43:95–102.
Qiao J, Gu C, Shang W, Du J, Yin W, Zhu M, Wang W, Han M, Lu W. Effect of green tea on pharmacokinetics of 5-fluorouracil in rats and pharmacodynamics in human cell lines in vitro. Food and Chemical Toxicology. 2011;49(6):1410-1415.
Roowi S, Stalmach A, Mullen W, Lean ME, Edwards CA, Crozier A. Green tea flavan-3-ols: Colonic degradation and urinary excretion of catabolites by humans. J Agric Food Chem. 2010;58:1296–1304.
Sadava D, Whitlock E, Kane S. The green tea polyphenol, epigallocatechin-3-gallate inhibits telomerase and induces apoptosis in drug-resistant lung cancer cells. Biochemical and Biophysical Research Communications. 2007;360(1):233-237.
Shanafelt T, Call T, Zent C, Leis J, LaPlant B, Bowen D, Roos M, Laumann K, Ghosh A, Lesnick C, Lee M, Yang C, Jelinek D, Erlichman C, Kay N. Phase 2 trial of daily, oral polyphenon E in patients with asymptomatic, Rai stage 0 to II chronic lymphocytic leukemia. Cancer. 2012;119(2):363-370.
Shervington A, Pawar V, Menon S, Thakkar D, Patel R. The sensitization of glioma cells to cisplatin and tamoxifen by the use of catechin. Molecular Biology Reports. 2008;36(5):1181-1186.
Shimizu M, Fukutomi Y, Ninomiya M, Nagura K, Kato T, Araki H, Suganuma M, Fujiki H, Moriwaki H. Green Tea Extracts for the Prevention of Metachronous Colorectal Adenomas: A Pilot Study. Cancer Epidemiology Biomarkers & Prevention. 2008;17(11):3020-3025.
Shimizu M, Shirakami Y, Sakai H, Yasuda Y, Kubota M, Adachi S, Tsurumi H, Hara Y, Moriwaki H. (−)-Epigallocatechin gallate inhibits growth and activation of the VEGF/VEGFR axis in human colorectal cancer cells. Chemico-Biological Interactions. 2010;185(3):247-252.
Shrubsole M, Lu W, Chen Z, Shu X, Zheng Y, Dai Q, Cai Q, Gu K, Ruan Z, Gao Y, Zheng W. Drinking Green Tea Modestly Reduces Breast Cancer Risk. Journal of Nutrition. 2008;139(2):310-316.
Singh BN, Shankar S, Srivastava RK. Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications. Biochem Pharmacol. 2011;82(12):1807-21.
Stalmach A, Troufflard S, Serafini M, Crozier A. Absorption, metabolism and excretion of Choladi green tea flavan-3-ols by humans. Mol Nutr Food Res. 2009;53:S44–S53.
Stearns M, Amatangelo M, Varma D, Sell C, Goodyear S. Combination Therapy with Epigallocatechin-3-Gallate and Doxorubicin in Human Prostate Tumor Modeling Studies. The American Journal of Pathology. 2010;177(6):3169-3179.
Stearns M, Wang M. Synergistic Effects of the Green Tea Extract Epigallocatechin-3-gallate and Taxane in Eradication of Malignant Human Prostate Tumors. Translational Oncology. 2011;4(3):147-156.
Tang S, Fu J, Shankar S, Srivastava R. EGCG Enhances the Therapeutic Potential of Gemcitabine and CP690550 by Inhibiting STAT3 Signaling Pathway in Human Pancreatic Cancer. PLoS ONE. 2012;7(2):e31067.
Trudel D, Labbé D, Araya-Farias M, Doyen A, Bazinet L, Duchesne T, Plante M, Grégoire J, Renaud M, Bachvarov D, Têtu B, Bairati I. A two-stage, single-arm, phase II study of EGCG-enriched green tea drink as a maintenance therapy in women with advanced stage ovarian cancer. Gynecologic Oncology. 2013;131(2):357-361.
Wang Q, Wang Y, Ji Z, Chen X, Pan Y, Gao G, Gu H, Yang Y, Choi B, Yan Y. Risk factors for multiple myeloma: A hospital-based case–control study in Northwest China. Cancer Epidemiology. 2012;36(5):439-444.
Wu H, Xin Y, Xu C, Xiao Y. Capecitabine combined with (-)-epigallocatechin-3-gallate inhibits angiogenesis and tumor growth in nude mice with gastric cancer xenografts. Experimental and Therapeutic Medicine. 2012;3(4):650-654. – (a)
Wu H, Xin Y, Xiao Y, Zhao J. Low-Dose Docetaxel Combined with (−)-Epigallocatechin-3-Gallate Inhibits angiogenesis and tumor growth in nude mice with gastric cancer xenografts. Cancer Biotherapy & Radiopharmaceuticals. 2012;27(3):204-209. – (b)
Zhang, Y., Wang, X., Han, L., Zhou, Y., & Sun, S. (2015). Green tea polyphenol EGCG reverse cisplatin resistance of A549/DDP cell line through candidate genes demethylation. Biomedicine & Pharmacotherapy, 69, 285–290. http://www.sciencedirect.com/science/article/pii/S075333221400211X
Zhao H, Zhu W, Xie P, Li H, Zhang X, Sun X, Yu J, Xing L. A phase I study of concurrent chemotherapy and thoracic radiotherapy with oral epigallocatechin-3-gallate protection in patients with locally advanced stage III non-small-cell lung cancer. Radiotherapy and Oncology. 2014;110(1):132-136.
Zhao H, Xie P, Li X, Zhu W, Sun X, Sun X et al. A prospective phase II trial of EGCG in treatment of acute radiation-induced esophagitis for stage III lung cancer. Radiotherapy and Oncology. 2015.http://www.ncbi.nlm.nih.gov/pubmed/25769379
Zhou D, Wang X, Feng Q. EGCG Enhances the Efficacy of Cisplatin by Downregulating hsa-miR-98-5p in NSCLC A549 Cells. Nutrition and Cancer. 2014;66(4):636-644.
