June, 2015 |386
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.
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.
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).
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).
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).
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.
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).
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.
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.
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