Introduction

With the worldwide cancer incidence rate suspected to increase from 12.7 million cases per year in 2008, to a staggering 21.4 million cases per year in 2030, cancer prevention and treatment is crucial (Global Cancer Facts & Figures 2nd Edition, 2011). Recently, the use of natural dietary compounds as anti-cancer agents has become a large area of exploration in the field of cancer research. Accumulating evidence highlights the anti-carcinogenic and chemopreventive role of the phytolexin resveratrol, a compound found in the skin of grapes, red wine, chocolate, and certain berries (Kundu & Surh, 2008).

An initial study on the use of resveratrol as an anti-carcinogenic agent found that the topical application of resveratrol prevented tumor formation in mice (Jang et al., 1997). More recent preclinical data provides evidence for resveratrol’s protective properties against a multitude of cancers including colon, prostate, breast, hepatic, pancreatic, gastric, melanoma, and lung cancer (Carter, D’Orazio & Pearson, 2014).  At the molecular and cellular levels, resveratrol can act on DNA and proteins to inhibit the initiation, promotion, and progression stages of carcinogenesis (Jang et al., 1997; Devi, 2004).  Such chemopreventive effects can be achieved through resveratrol’s pro-apoptotic, anti-proliferative, anti-oxidant, anti-inflammatory, and anti-angiogenic properties (Carter, D’Orazio & Pearson, 2014; Boyce, Doehmer & Gooderham, 2004; Le Corre, Chalabi, Delort, Bignon & Bernard-Gallon, 2005).  In addition to its role as a chemopreventive agent, resveratrol has been shown to sensitize cancer cells to a number of chemotherapeutic agents, thus enhancing their chemotherapeutic potential (Fulda & Debatin, 2004; Santandreu, Valle, Oliver & Roca, 2011).

A concern for the implementation of resveratrol as part of cancer therapy is its bioavailability. Maintaining a clinically relevant dose is challenging as resveratrol is rapidly metabolized in the body (Walle et al., 2004).  However, recent research has analyzed different ways to improve resveratrol’s bioavailability in the human body (Howells et al., 2011; Dellinger, Garcia &  Meyskens, 2014; la Porte et al., 2010).  The objective of this paper is to conduct a review of the pre-clinical and clinical evidence surrounding the use of resveratrol as a chemopreventive agent in cancer, its bioavailability in humans, and its ability to sensitize cancer cells to conventional chemotherapeutics.

 

Chemopreventive Properties

Apoptosis & Cell Cycle Arrest

Human cell line studies have highlighted the role of resveratrol as a pro-apoptotic and anti-proliferative phytochemical against a variety of cancers including colon, pancreatic, breast, lung, prostate, gastric, and skin cancer cell lines (Temraz, Mukherji & Shamseddine, 2013; Shamim et al., 2012; Shi et al., 2011; Luo, Yang, Schulte, Wargovich & Wang, 2013; Kai, Samuel & Levenson, 2010; Chung, Lim & Lee, 2013; Kim, 2012).  Such studies have focused on understanding resveratrol’s underlying pro-apoptotic and anti-proliferative mechanisms, with most activity surrounding interactions with DNA and proteins, including the activation of tumour suppressor protein p53, activation of cell cycle inhibitors p21 and p27, and the up-regulation of pro-apoptotic proteins such as Bax (Malhotra, Nair & Dhawan, 2012).  Moreover, resveratrol has been found to inhibit major pathways involved in cell growth and migration including the WNT, MAPK-ERK, and PI3K-AKT signalling pathways (Refer to Table 1 for further details) (Azmi et al., 2013; Gescher, Steward & Brown, 2013; Carter, D’Orazio & Pearson, 2014).

Similarly, in vivo studies using lung, skin, and pancreatic mouse models demonstrate that resveratrol administration leads to a reduction in tumour growth (Malhotra, Nair & Dhawan, 2012; Gescher, Steward & Brown, 2013; Carter, D’Orazio & Pearson, 2014).  Although one study found resveratrol to have pro-apoptotic effects on a normal pancreatic cell line, the study failed to provide data for this observation, or elaborate on the extent of cytotoxicity (Azmi et al., 2013).  Multiple other studies suggest that resveratrol preferentially targets cancer cells, while simultaneously protecting normal host cells from unwanted growth arrest and apoptosis (Luo, Yang, Schulte, Wargovich & Wang, 2013; Rusin, Zajkowicz & Butkiewicz, 2009; Tyagi et al., 2011).

 

Antioxidant

Low dose resveratrol (<50μM) has been shown to promote antioxidant properties by regulating the generation of reactive oxygen species, while high doses are suggested to promote pro-oxidant activity (Shrotriya, Agarwal & Sclafani, 2015; Luo, Yang, Schulte, Wargovich & Wang, 2013). Studies using cell line and animal models of skin, colon, lung, and hepatic cancers propose that resveratrol enhances the activity of the transcription factor Nrf-2, which stimulates the expression of antioxidant enzymes such as glutathione S-transferase, catalase, glutathione peroxidase, and superoxide dismutase (Refer to Table 2 for further details) (Shrotriya, Agarwal & Sclafani, 2015; Chiou et al., 2011; Tan et al., 2012; Khan et al., 2013; Bishayee, Barnes, Bhatia, Darvesh & Carroll, 2010). Hence, this is important given that accumulating evidence proposes an association of various cancers with low activities of antioxidant enzymes (Arsova-Sarafinovska et al., 2009; Sharma, Tripathi, Satyam & Kumar, 2009).

 

Anti-inflammatory & Anti-angiogenesis Properties

Resveratrol has also been shown to have anti-inflammatory and anti-angiogenic properties. Since tumor cells utilize the body’s inflammatory response mechanisms to induce angiogenesis for survival, reduced inflammatory responses may help induce tumor cell death by preventing angiogenesis and cell proliferation (Dalgleish & Haefner, 2006; Bishayee, Barnes, Bhatia, Darvesh & Carroll, 2010). Resveratrol has been shown to down-regulate the expression of the pro-inflammatory enzyme COX-2 in a hepatic cancer rat model, and reduce the generation of the inflammatory mediator nitric oxide in colon cancer cell lines (Bishayee, Barnes, Bhatia, Darvesh & Carroll, 2010; Panaro, Carofiglio, Acquafredda, Cavallo & Cianciulli, 2012). Additionally, a study found that resveratrol exerts anti-angiogenic effects in a melanoma cell line by decreasing levels of vascular endothelial growth factor (Trapp, Parmakhtiar, Papazian, Willmott & Fruehauf, 2010). In humans with prostate cancer, resveratrol inhibits the activities of metastasis-associated antigen leading to p53 activation, as well as reduced invasion and angiogenesis (Refer to Table 3 for further details) (Levenson, Kumar & Zhang, 2014).

 

Prevention of Cancer Onset

In addition to the protective properties that resveratrol has against existing cancers, it can also play a role in preventing cancer onset. Cancer prevention often involves inhibition of cytochrome P450 (CYP) enzymes that can activate environmental carcinogens. For example, a group of CYP enzymes metabolize alcohol into acetaldehyde, which then interacts with DNA and increases the risk of head and neck cancers (Chow et al., 2010; Shrotriya, Agarwal & Sclafani, 2015). In lung, breast, and colon cancer cell lines, resveratrol was found to reduce CYP1A1 mRNA accumulation by approximately 50%, thus reducing the amount of enzyme available to activate carcinogens (Perdew et al., 2010). Moreover, CYP enzyme activity was measured in a clinical study consisting of 42 healthy volunteers taking 1g of resveratrol daily for four weeks. Their results suggest that pharmacologic doses of resveratrol have the ability to upregulate or down-regulate CYP enzyme levels. This can interfere with the metabolism of cholesterol lowering statins and chemotherapeutics, thus necessitating caution before administering resveratrol in clinical settings (Refer to Table 4 for further details) (Chow et al., 2010).

 

Bioavailability

Due to resveratrol’s rapid metabolism, a challenge for clinical implementation is the difficulty in maintaining a therapeutically relevant level of resveratrol in the blood (Singh, Ndiaye & Ahmad, 2014).  Bioavailability studies have shown that trans-resveratrol, the biologically active form, is quickly absorbed into the circulation, with maximal plasma concentrations achieved after 30 minutes (Bishayee, 2009).  However, phase II metabolism in the liver rapidly catabolizes resveratrol into glucuronide and sulfate conjugates (Walle et al., 2004).  Consequently, serum analysis 4 hours after the administration of a dietary-relevant dose of resveratrol at 25mg/70kg reveals that only 2% of total resveratrol remains in its unmodified form, indicating low oral bioavailability (Goldberg et al. 2003).  Moreover, in a recent clinical trial, where a high dose of resveratrol (5g) was administered to 10 healthy participants for 29 days, plasma resveratrol concentrations were measured to be approximately 4μM.  This concentration is below levels previously shown to have chemopreventive effects in preclinical studies (Brown et al., 2010; Boocock et al., 2007).

Despite its inherently low blood concentration, resveratrol can be rapidly absorbed to exert chemopreventive effects (Walle et al., 2004). Urinary excretion data determined that more than 70% of a single 100mg dose of resveratrol was absorbed into cells, suggesting that intratissular and intracellular levels may be higher than those measured in the plasma  (Walle et al., 2004; Patel et al., 2013). Moreover, recent evidence suggests that certain resveratrol conjugates can be enzymatically returned to their trans-resveratrol form, or may even promote anti-proliferative effects on their own (Zhu et al., 2012).

Modifications to resveratrol have been made to address the difficulties surrounding its bioavailability and rapid metabolism. For example, with a single dose of SRT501, a micronized oral form of resveratrol, mean plasma levels were 3.6 times higher than a similar dose of non-micronized resveratrol (Howells et al., 2011).  It may also be useful to modify the molecular structure of resveratrol.  Pterostilbene, a dimethylated analogue of resveratrol, is metabolized slower, thus contributing to improved bioavailability (Dellinger, Garcia &  Meyskens, 2014).  In addition, a study examining the pharmacokinetics of resveratrol revealed that when taken with a high fat meal, the maximal plasma concentration of resveratrol was reduced (la Porte et al., 2010). Therefore, through micronization, development of resveratrol analogues, or avoidance of a high fat diet, it may be possible to address resveratrol’s bioavailability concerns.

 

Clinical Trials

All clinical trials to date are conveniently summarized in Table 5 of the Appendix. From the limited number of clinical trials, there appears to be conflicting results; however, the positive results justify looking further into resveratrol as a potential chemopreventive agent.

A randomized controlled trial of participants with colorectal cancer and hepatic metastasis (n=9) found that receiving 5g SRT501 for 14 days resulted in a 39% increase in cleaved caspase 3.  The study also analyzed other common markers of apoptosis, but found no significant difference in levels between the two groups. While this evidence is not conclusive, it does suggest that resveratrol may promote apoptosis in humans (Howells et al., 2011).

Another study of patients with colorectal cancer (n=20) presented positive evidence for resveratrol as a chemopreventive agent. In this study, daily doses of 0.5g or 1.0g were administered over eight days to participants prior to surgical resection. A comparison of pre-intervention and post-intervention tissue samples demonstrated a significant 5% reduction in Ki-67 staining, a marker of tumour cell proliferation. Despite the small dose, high enough resveratrol concentrations were achieved within the gastrointestinal tract to produce anti-carcinogenic effects (Patel et al., 2010). Due to the small study populations and high variability between participants in existing clinical trials, it is difficult to make clear clinical recommendations on the effectiveness of resveratrol as a cancer preventive or therapeutic agent.

Some evidence suggests that resveratrol may have harmful adverse effects.  One study consisting of participants with relapsed or refractory multiple myeloma (MM) (n=24) found that doses of 5.0g SRT501 combined with bortezomib produced serious adverse effects.  During the study, five serious adverse events of renal toxicity were observed in addition to two deaths, one potentially related to the treatment, causing researchers to end the study early  (Popat et al., 2013).  Results this harmful have not been found in other studies using a 5g dose of SRT501; Howells et al. found mild gastrointestinal adverse effects reported by participants. As well, in a repeat dose study with healthy volunteers (n=40), only mild short-term gastrointestinal adverse effects were noted in participants taking 2.5g or 5g doses of resveratrol for 29 days (Brown et al., 2010).  It has been reported that about 50% of patients with MM develop renal impairment as the disease progresses. Additionally, three out of the five participants who experienced renal toxicity as an adverse event began the study with elevated blood creatinine levels, potentially indicating the presence of pre-existing renal dysfunction (Popat et al., 2013). Thus, participants in the Popat et al. study may have been at a higher baseline risk of developing renal failure.  Nonetheless, as a precaution, we propose that resveratrol should not be used in those with pre-existing kidney conditions. Despite the unexpected finding of renal toxicity in MM patients taking SRT501, these results do not indicate that SRT501 or resveratrol are unsafe for other cancer populations. This, however, does require further research into the safety and dosing of resveratrol.

 

Chemosensitization of Resveratrol

Based on evidence from clinical trials to date, resveratrol may not be sufficiently efficacious to be considered as an alternative to conventional cancer therapy; however, it does have the potential to be integrated into existing cancer treatment regimens. Accumulating evidence highlights resveratrol’s role as a chemosensitizing agent to a variety of chemotherapeutic drugs. In vitro studies with melphalan, for instance, have demonstrated that resveratrol can sensitize human breast cancer cells to melphalan-induced apoptosis, S-phase cell cycle arrest, and caspase activation (Casanova et al., 2012). Additionally, resveratrol was found to enhance the effects of cyclophosphamide (CPA) in human breast cancer cell lines; thus, a lower CPA dosage is required to achieve therapeutic effects. This minimizes CPA-associated chemotoxicity and maximizes anti-cancer effects (Singh et al., 2011).

Similarly, in vivo studies demonstrated resveratrol’s ability to decrease the required dose of cisplatin, gefitinib and paclitaxel in mice implanted with human lung cancer cells (Zhao, Bao, Qi & You, 2010). In a murine model of human pancreatic cancer, resveratrol was shown to sensitize pancreatic cancer cells and potentiate the effects of gemcitabine through the inhibition of NF-kB activation and expression of cell survival proteins (Harikumar et al., 2010).

Various chemotherapeutic agents exert pro-oxidant activity, but despite resveratrol’s anti-oxidant properties, no antagonistic effects were observed in the aforementioned studies.  Some studies, however, reported the potential for resveratrol to suppress apoptosis induced by daunorubicin and two mitotic inhibitors, paclitaxel and vincristine (Gupta, Kannappan, Reuter, Kim & Aggarwal, 2011).

Resveratrol’s chemosensitization effects may also be dependent on dosage; in vitro studies involving human colon cancer cells demonstrated that resveratrol synergistically promoted 5-fluorouracil (5-FU)-mediated apoptosis at high doses of both resveratrol (200μM) and 5-FU (120μM), as well as with lower doses of both resveratrol (15μM) and 5-FU (0.5μM) (Chan, Phoo, Clement, Pervaiz & Lee, 2008; Mohapatra et al., 2011). Although resveratrol has the potential to be used in combination with various chemotherapeutic agents, further studies are needed before this combination therapy could be implemented in clinical settings.

 

Discussion

This review summarizes current evidence on resveratrol as a factor with pro-apoptotic, anti-proliferative, anti-inflammatory, anti-angiogenic, antioxidant and chemosensitizing properties. Cell line and animal studies have highlighted this phytochemical’s efficacy against a variety of cancers including colon, pancreatic, breast, lung, prostate, gastric, hepatic and skin cancer. Due to its many modes of anti-cancer activity, from changes in DNA expression to protein interactions and pathway-modulatory activity, resveratrol has garnered significant attention in the field of cancer research.

Although cell line and animal studies have suggested resveratrol to be efficacious against cancer cells and tumours, clinical data on resveratrol’s chemopreventive potential in humans is conflicting. Small samples and unstandardized populations across clinical trials, in addition to evidence suggesting potential adverse effects of resveratrol, highlight the need for further human research.  Thus, the current research on resveratrol does not permit a clinical recommendation to be made, except that as a precautionary measure, it should not be used in patients with pre-existing renal conditions (Popat et al., 2013).

Future research should focus on evaluating the effectiveness and safety of resveratrol in a variety of different cancer types. Moreover, a look into resveratrol analogues with significantly more potency and improved bioavailability, such as pterostilbene, are also recommended.  Pterostilbene has been shown to have more potent inhibitory effects on the growth of three colon cancer cell lines, as measured by levels of cleaved caspase-3 (Nutakul et al., 2011; Dellinger, Garcia &  Meyskens, 2014).  Ultimately, in clinical practice, resveratrol will likely be used as an adjuvant therapy; therefore, beyond researching resveratrol as a monotherapeutic agent, future studies should further investigate resveratrol in combination with classic chemotherapeutic agents. In addition, since resveratrol displayed antagonistic effects with mitotic inhibitors such as paclitaxel and vincristine, we recommend further exploring the interaction of resveratrol with mitotic inhibitors (Gupta, Kannappan, Reuter, Kim & Aggarwal, 2011).

 

Conclusion

Additional studies are needed to further investigate and understand resveratrol’s chemopreventive effects when combined with chemotherapeutic agents.  Nonetheless, it is evident that the difficulties surrounding resveratrol’s bioavailability can be addressed and that there are potential benefits for implementing resveratrol as a combinatory therapy in clinical settings in the future.

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Introduction

Forty percent of Canadians develop cancer in their lifetime, and twenty-five percent of these cases are fatal (Canadian Cancer Society 2014). The standards of care for cancer are chemotherapy, radiation, and/or surgery, because these modalities have demonstrated the highest treatment efficacy in clinical practice (Canadian Cancer Society 2012, Canadian Cancer Society 2015). However, patients diagnosed with chemotherapy- and radiotherapy-resistant cancers face treatment challenges (Li 2014). Thus, treatments adjuvant to conventional therapy are being explored.

Turmeric (Curcuma longa) is a plant native to Asia (Shishodia 2005). This nutraceutical has garnered interest as a complementary cancer therapy, as observational evidence has demonstrated low rates of colorectal, prostate, and lung cancers in Asia, where high amounts of turmeric are consumed (Aggarwal 2003, Lao 2006, Sinha 2003).

Curcumin (diferuloylmethane) is the most thoroughly researched active component of turmeric (Chattopadhyay 2004, Lao 2006, Shishodia 2005). Research evidence demonstrates that curcumin is more effective when used in conjunction with chemotherapy than as a stand-alone therapy (Kusuhara 2012, Lin 2007). This is due to its ability to downregulate resistance proteins (Guo 2014, Rana 2015, Roy 2014) and modulate cancer stem cells, which are both integral mechanisms to cancer resistance, metastasis, and recurrence (Buhrmann 2014, Shakibaei 2014). Moreover, curcumin antagonizes many of chemotherapy’s negative side effects such as promotion of cell proliferation through NF-kB (Cabrespine-Faugeras 2010, Melisi 2007). This paper investigates the clinical potential for curcumin use with conventional therapy to improve treatment outcomes in a variety of cancers.

 

General Cancer Pathways

Figure 1: Cellular pathways involved in cancer pathology and the effects of curcumin and chemotherapy

This diagram illustrates the effects of curcumin and chemotherapy on various molecules involved in cancer. Curcumin decreases angiogenesis, tumour cell proliferation, metastasis, and cancer cell survival. Nuclear factor-kappaB (NF-kB) activation facilitates tumour cell survival by downregulating caspase-3, -6, and -7, which are factors integral to cellular apoptosis (Cabrespine-Faugeras 2010, Melisi 2007). Paradoxically, chemotherapeutic drugs often upregulate NF-kB (Kamat 2009, Tharakan 2010), while curcumin inhibits it (Cabrespine-Faugeras 2010). NF-kB upregulates the inflammatory factor TNF-, which leads to increased cellular proliferation. Curcumin and chemotherapy drugs inhibit Bcl-2 – an apoptosis suppressing protein – by upregulating tumour suppressor protein p53. In turn, p53 upregulates Bcl-2-associated X protein (BAX), which directly antagonizes Bcl-2 (Cabrespine-Faugeras 2010). The ratio of BAX to Bcl-2 determines if a cell will survive or undergo apoptosis; curcumin increases this ratio, leading to apoptosis (Jiang 2015). Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2)/neu signaling pathways lead to upregulation of Protein Kinase B (p-Akt) which causes angiogenesis, prevents cell cycle arrest, and thus increases cancer cell survival (Cabrespine-Faugeras 2010). Curcumin inhibits EGFR and HER2/neu thereby decreasing both angiogenesis and cell survival. Cyclooxygenase-2 (COX-2) is upregulated by chemotherapeutic drugs. It upregulates vascular endothelial growth factor (VEGF), which stimulates angiogenesis (Cabrespine-Faugeras 2010). This happens via upregulation of matrix metalloproteinases (MMPs), a critical step for metastasis (Cabrespine-Faugeras 2010, Chen 2014, Lin 2009). MMPs are also activated by Rac1 (Chen 2014). Curcumin inhibits both COX-2 and VEGF, thereby suppressing angiogenesis (Cabrespine-Faugeras 2010). Curcumin also downregulates the expression of multidrug-resist proteins, MRP1 and PGP1, which desensitize receptors to chemotherapy (Roy 2014).

 

 

Breast Cancer

Bayet-Robert and colleagues (2010) administered a combined treatment of oral curcumin and Docetaxel to patients with advanced and metastatic breast cancer. One third of patients initially had inoperable cancers that became operable by the end of the study. Furthermore, none of the patients demonstrated disease progression. Of the nine patients evaluated for response, one patient had no residual tumour, six partially responded to treatment, and two remained in a stable disease state. Patients had lowered tumour marker and VEGF levels, indicating reduced cancer cell survival and angiogenesis (Bayet-Robert 2010). In healthy human subjects, breast cancer resistance protein (BCRP)-expressing cells treated with curcumin had increased uptake of sulphasalazine – an anti-inflammatory drug that inhibits NF-kB activation (Kusuhara 2012). BCRP plays a role in chemoresistance, thus, this study suggests that curcumin may act as a chemosensitizer in humans (Kusuhara 2012).

Curcumin increased breast cancer cell sensitivity to other chemotherapeutic drugs, including MMC, Doxorubicin, Tamoxifen, Paclitaxel, Trichostatin A and 5-Fluorouracil (5-FU), in in vitro and in vivo animal studies. In turn, curcumin can reduce the drug concentrations necessary to achieve equivalent drug efficacy (Aggarwal 2005, Chen 2013, De Gasperi 2009, Jiang 2013, Kang 2009, Vinod 2013, Yan 2013, Zhou 2009, Zhou 2011). Curcumin may also reduce side effects of chemotherapeutic drugs, such as weight loss, renal toxicity, and cytotoxicity (Zhou 2009, Zhou 2011).

Curcumin has demonstrated antiproliferative, anti-angiogenic, anti-metastatic, and pro-apoptotic effects in vivo and in vitro when used alone or in conjunction with chemotherapeutic drugs in hormone receptor-positive and -negative breast cancers (Bachmeier 2007, Chen 2013, De Gasperi 2009, Liu 2009, Shao 2002, Vinod 2013, Yan 2013, Zhou 2009). For instance, MMC with curcumin reduced tumor weight by 60.4% more than MMC alone in in vivo xenografts (Zhou 2011). A 21% reduction in VEGF levels was also observed after six cycles of combined Docetaxel and curcumin treatment (Bayet-Robert 2010). Curcumin suppressed the Paclitaxel-induced expression of antiapoptotic (e.g. Bcl-2), proliferative (e.g. COX-2), and metastatic proteins (e.g. VEGF and MMP-9) in vitro in chemotherapy-resistant cells, while significantly decreasing metastasis in in vivo xenografts (Aggarwal 2005).

 

Colorectal Cancer

When administered alone or alongside chemotherapy drugs, curcumin has effectively suppressed inflammatory factors such as TNF-α, thus upregulating tumour suppressors, inhibiting cancer cell proliferation, and causing cancer cell apoptosis in in vitro and in vivo models (Guo 2013, Guo 2015, Lim 2014, Wang 2015). Toden et al. (2015) found that curcumin sensitizes colorectal cancer cells to 5-FU in 5-FU-resistant cells and xenografts. Curcumin’s ability to enhance the apoptotic and anti-proliferative effects of chemotherapeutic drugs such as 5-FU and Oxaliplatin is significant in the treatment of both non-resistant and resistant cancers (Guo 2014, Rana 2015). Curcumin’s chemosensitizing effects modulate the activity of cancer stem cells, which are thought to cause cancer cell resistance (Buhrmann 2014, Shakibaei 2014). Furthermore, a human study found that curcumin promotes positive outcomes in colorectal cancer patients, such as weight gain and upregulation of the tumour suppressor, p53 (He 2011).

 

 

Pancreatic Cancer

Pancreatic cancer is aggressive and has an overall poor prognosis (Mayo Foundation 2015). It is often detected at advanced stages, and its 5-year observed survival rate is 15-20% (Canadian Cancer Society 2015). Animal studies demonstrate that curcumin can work synergistically with Gemcitabine (Kunnumakkara 2007); however, human studies have shown conflicting results.

In a Phase I/II trial, patients receiving curcumin and Gemcitabine reported severe gastrointestinal side effects such as diarrhea, nausea and intractable abdominal pain, as well as poor tolerability (Epelbaum 2010). It is unclear whether these side effects can be attributed to the progression of late-stage cancer and chemotherapy, or to curcumin alone, as there was no control group (Epelbaum 2010). A study conducted with Gemcitabine-resistant patients found that curcumin was well-tolerated (Kanai 2011). Median compliance was 100% and zero patients withdrew due to intolerability. The median survival time was 161 days. Several patients reported reduced chemotherapy-related side effects such as fatigue, pain, and constipation (Kanai 2011). Some patients exhibited partial response (Dhillon 2008) or stable disease (Kanai 2011) in some studies; however, these effects are not applicable to all patients (Dhillon 2008, Kanai 2011).

 

Leukemia

Ghalaut et al. (2012) investigated the effect of oral consumption of curcumin in leukemia patients undergoing Imatinib chemotherapy in comparison to those undergoing chemotherapy alone. Treatment potentiated a favourable haematological response (i.e. lowered platelet, white blood cell, and immature granulocyte and basophil count) and decreased nitric oxide levels — an inducer of tumour growth, invasion, and metastasis (Ghalaut 2012). Curcumin has also been shown to decrease tumour growth rate and promote organism survival in xenograft mice models (William 2008, Yu 2013, Zunino 2013). In vitro studies have demonstrated the ability of curcumin to potentiate the effects of chemotherapeutic drugs including Tamoxifen (Pedroso 2013), L-asparaginase (Wang 2012), Methotrexate (Dhanasekaran 2013), Etoposide (Papiez 2014), Lonidamine (Sanchez 2010), and arsenic trioxide (Sanchez 2010), but not Silibinin (Pesakhov 2010) and Cisplatin (Sanchez 2010).

 

Bladder Cancer

Using an orthotopic mouse model, Tharakan and colleagues (2010) found that curcumin potentiates the apoptotic and anti-proliferative effects of Gemcitabine. Curcumin decreased biomarkers of proliferation and angiogenesis such as COX-2 and VEGF, respectively, with maximal effectiveness using combination therapy (Tharakan 2010). A study conducted in in vitro and xenograft models, using curcumin and Bacillus Calmette-Guerin (BCG), a standard drug for bladder cancer, demonstrated similar results with combination therapy being more effective than either treatment alone (Kamat 2009). Similar results have been achieved in an in vivo xenograft mouse model (Chadalapaka 2008). Tian and colleagues (2008) found that curcumin had a greater inhibitory effect on NF-kB than Cisplatin, but no synergistic effect was found between the two.

 

Liver cancer

Studies using Hepatocellular Carcinoma (HCC) xenografts have shown that intravenous injection or oral consumption of curcumin may produce anti-angiogenic and anti-proliferative effects on tumour development (Anand 2012, Cui 2006, Dai 2013, Ning 2009, Yoysungneon 2008). Curcumin has also demonstrated synergistic anti-cancer effects when administered in conjunction with chemotherapeutic drugs such as Doxorubicin (Zhao 2014) and Paclitaxel (Ganta 2010) in in vivo animal models, and Cisplatin (Notarbartolo 2005), 5-FU (Zhu 2013), and Adriamycin (Qian 2011) in vitro. Synergistic effects were also seen in combined treatment with anti-angiogenic agents such as Leflunomide and Perindopril in in vivo mice models (Nasr 2014).

 

Cancers of the Head and Neck

In in vivo xenografts, curcumin inhibited tumour development (LoTempio 2005, Odot 2004, Wang 2008, Zhu 2012) and increased organism survival (Clark 2010) when compared to control mice. Additionally, curcumin potentiated the effects of radiotherapy (Chiang 2014, Khalif 2009) and chemotherapeutic drugs 5-FU (Tian 2012) and Cisplatin (Duarte 2010) in mouse models.

 

Uterine and Cervical Cancer

Sreekanth et al. (2011) found that, in xenografts and chemically-induced mouse models, curcumin enhanced Paclitaxel’s antitumour effect by decreasing expression of anti-apoptotic factors NF-kB and p-Akt. Thus, combination therapy led to decreased tumour incidence and volume when compared to groups treated with either Paclitaxel or curcumin alone (Sreekanth 2011). Additionally, curcumin sensitized Cisplatin-resistant human cervical cancer cells to Cisplatin through modulation of multidrug-resistant proteins, such as MRP1 (Roy 2014). Furthermore, in a xenograft study using a hormone therapy called Letrozole, curcumin was shown to synergistically enhance inhibition of endometrial tumour growth (Liang 2009).

 

Prostate Cancer

A study on human prostate cancer cells found that curcumin alone inhibited 20% of the production of prostate-specific antigen – a biomarker of inflammation in the prostate (Ide 2010). These results have also been seen in xenografts injected with human prostate cancer cells (Dorai 2001). Additionally, studies examining xenografts and cancer cell lines found that curcumin sensitizes both hormone-resistant and hormone-sensitive prostate cancer cells to TNF-related apoptosis-inducing ligand (TRAIL), a cytokine that induces apoptosis (An 2014, Andrzejewski 2008). The combined therapy of TRAIL and curcumin induced apoptosis in cancer cells by inhibiting anti-apoptotic p-Akt and NF-kB (Andrzejewski 2008). Furthermore, curcumin and chemotherapeutic drugs, such as Paclitaxel, have demonstrated synergistic effects in reducing angiogenesis, proliferation, and metastasis (Cabrespine-Faugeras 2010).

 

Lung Cancer

In human lung cancer cell lines, curcumin reduced metastasis by inhibiting the Rac1 signaling pathway and MMP-2 and MMP-9 expression (Chen 2014a). In another in vitro study, curcumin was found to increase sensitivity of cells that were initially resistant to Cisplatin, leading to reduced cell proliferation (Chen 2014b). Similar effects were seen with Docetaxel in non-small cell lung cancers (Yin 2012).

 

Cancers with Inadequate Evidence

Clinical recommendations cannot be made for the use of curcumin as a complementary therapy for brain, gastric, skin, kidney, and bone cancers.

Brain cancer studies conducted on human glioma cell lines have shown that curcumin exerts an apoptotic and chemosensitizing effect by reducing the activity of transcription factors such as NF-kB (Dhandapani 2007). However, curcumin does not cross the blood-brain barrier unless delivered in a solubilized form, making it unsuitable as an adjuvant therapy for brain cancers (Purkayastha 2009).

Several studies conducted using animal models and human gastric cancer cell lines have shown the benefits of curcumin in the treatment of gastric cancer (Cai 2013, Deshpande 1997, Huang 1994, Yu 2011). Yu and colleagues (2011) found that curcumin reversed chemoresistance by downregulating NF-kB in vitro. They found that curcumin, in conjunction with Etoposide and Doxorubicin, suppresses cancer cell growth more effectively than these chemotherapeutics alone (Yu 2011). Nonetheless, as there are no human studies and very few in vivo studies for curcumin in gastric cancer, it is difficult to make clinical recommendations.

There are very few studies investigating the effects of curcumin in conjunction with chemotherapy in skin, kidney, and bone cancers. Most available studies are in vitro, and there is a significant lack of human or animal studies. Thus, there is insufficient evidence to make clinical recommendations for these cancers.

 

Bioavailability, Administration Methods & Analogues

When free curcumin is administered, it exhibits low bioavailability due to its low water solubility, high rate of metabolism, and poor absorption in the human body, thus limiting its potential anti-cancer effects (Anand 2007, Heger 2013). In order to reach a therapeutic dose in cancer patients, curcumin analogues and alternative administration methods aside from oral delivery are being explored.

Various forms of nanoparticles have been tested in colorectal (Chuah 2014), pancreatic (Bisht 2010, Yallapu 2013), breast (Yallapu 2012), lung (Yin 2013), and liver cancers (Duan 2010, Yen 2010). Other delivery methods such as liposomes have been tested in pancreatic (Mach 2009) and lung cancers (Rahman 2012); microspheres in lung cancer (Cao 2011); micelles in colorectal cancer (Abouzeid 2013); polymers in prostate (Boztas 2013), breast (Bansal 2014, Liu 2013), and colorectal cancers (Chen 2012); and implants in breast cancer (Bansal 2014).

Other studies have combined these administration methods in forms such as solid lipid nanoparticles to further improve potency (Francis 2014, Mulik 2010, Wang 2013). Kanai et al. (2013) were the first to employ a novel curcumin administration method in humans through a nanoparticle called Theracurmin. Theracurmin has reduced particle size by over 100 times, addressed the issue of inadequate aqueous solubility, and employed a sustained drug release system. These strategies have increased bioavailability and reduced toxicity in animal as well as human subjects (Kanai 2013).

The use of synthetic analogues is being explored as a possible alternative to overcome the issue of limited bioavailability of curcumin. By making substitutions to various functional groups, analogues can exhibit enhanced therapeutic efficacy (Adams 2004). Examples of analogues that have been developed are HO-3867 (Dayton 2010) for lung, colon, liver, breast, and ovarian cancers, DM-1 and DM-2 (Faião-Flores 2012) for breast cancer, and D6 for melanoma (Rozzo 2013). Generally, these studies have demonstrated positive effects on bioavailability, such as increased uptake, higher serum levels, and increased accumulation in target organs (Adams 2004, Dayton 2010, Faião-Flores 2012, Rozzo 2013). Furthermore, this improved bioavailability results in reduced angiogenesis, cancer cell survival, tumour proliferation, and metastasis, and downregulation of multidrug resistance (Adams 2004, Dayton 2010, Faião-Flores 2012, Rozzo 2013). Human studies that test the clinical utility of these methods are required.

 

Dosing & Safety

Several human studies have investigated optimal dosing and dose-limiting toxicities of orally administered curcumin in patients undergoing chemotherapy and in healthy subjects. Some studies demonstrated that patients can tolerate up to 8g/day of orally delivered curcumin in capsule form (Cheng 2001, Dhillon 2008, Kanai 2011), while other studies suggested that the dose may lead to gastrointestinal side effects and lack of compliance due to bulkiness (Bayet-Robert 2010, Epelbaum 2010, Lao 2006). Regardless, when administered orally, the dose of 8g/day is insufficient to reach systemic bioavailability as measured via serum concentrations (Epelbaum 2010).

 

Limitations

The current literature describing the therapeutic effects of curcumin is thorough for certain cancers, while it is limited for others – particularly those with low prevalence. In general, animal studies demonstrate overwhelmingly positive results, but the low bioavailability of free curcumin limits its clinical utility as an anti-cancer therapy in humans. Although some novel methods have been studied to address bioavailability, further research is required.

Moreover, the literature on curcumin as a complementary chemotherapy is quite heterogeneous, making it difficult to compare and amalgamate study results and come to a general conclusion. Factors such as administration method, dosing, analogue type, follow-up period, and outcome measures should be standardized in future research.

 

Clinical Recommendation

A clinical recommendation for the use of curcumin cannot be made at this time due to inadequate evidence and the continued challenges associated with bioavailability.

 

 

 

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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.

1. 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.

 

2. 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).

 

3. 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 p21^Cip1 and p27^Kip1 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).

 

4. 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.

 

6. 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).

 

7. 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.

 

8. 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.

 

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