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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