LWW_CEJ_200649 Review article 1
Polyphenols as a chemopreventive agent in oral carcinogenesis: putative mechanisms of action using in-vitro and in-vivo test systems Carolina F. Gomes de Mouraa, Juliana Nogutia, Gustavo P. Pacheco de Jesusa, Flavia A. P. Ribeirob, Fernanda A. Garciab, Andrea P. B. Golluckec, Odair Aguiar Jrb and Daniel A. Ribeiroa,b Polyphenols are present in foods and beverages, being related to sensorial qualities such as color, bitterness, and astringency, which are relevant in products such as wine, tea, and grape juice. These compounds occur naturally in forms varying from simple phenolic acids to complex polymerized tannins. Oral cancer is the most common head and neck cancer, and it often has a poor prognosis owing to local tumor invasion and frequent lymph node metastasis. Nowadays, chemoprevention is considered as a promising approach for controlling cancer as a result of specific natural products or synthetic agents able to suppress, reverse, or even prevent premalignancy before transformation into invasive cancer. The use of polyphenols as a chemopreventive agent is a suitable tool for modulation of the oral carcinogenesis process. The aim of this article is to present data generated from the use of polyphenols as a chemopreventive agent in oral carcinogenesis using in-vivo and in-vitro test systems. These results have shown that polyphenols are able to
exert some chemopreventive action as a result of inducing cellular death, apoptosis, inhibition of tumor growth, and antioxidative properties. Therefore, this area warrants further investigation as a new approach that would apply not only to polyphenols but also to other phytochemicals used as promising therapeutic agents against oral human diseases, especially cancer. European Journal of Cancer c 2012 Wolters Kluwer Health | Prevention 00:000–000 Lippincott Williams & Wilkins.
The alleged knowledge that polyphenols are associated with protection against diseases has generated particular interest. Meanwhile, in western countries, the intake of fruits and vegetables, main sources of polyphenols, is considered to be insufficient. Consequently, supplementation appears as a viable alternative. In 2009, Dickinson et al. (2009) published an online survey conducted in 2007 by Ipsos Public Affairs for the Council for Responsible Nutrition (CRN), a trade association representing the dietary supplement industry. The survey asked 900 physicians and 277 nurses about their use of dietary supplements. The authors found that 72% of physicians and 89% of nurses used dietary supplements, on a regular, occasional, and seasonal basis. Regular use was reported by 51% of physicians and 59% of nurses. Moreover, 79% of physicians and 82% of nurses stated that they recommended supplements to their patients, including the ones who did not use supplements themselves. The findings are in accordance with national surveys, including the National Health and Nutrition Examination Survey (NHANES, 1999–2000). The dietary supplement product most commonly used was the multivitamin, with or without minerals. Among the nonvitamin/mineral products, physicians and nurses reported the consumption of green tea, fish oil, glucosamine, soy, flax seed, chondroitin, and Echinacea as
Polyphenols in foods and beverages are related to sensorial qualities such as color, bitterness, and astringency, which are relevant in products such as wine, tea, and grape juice (EsSafi et al., 2000; Scalbert and Williamson, 2000; Shi et al., 2003; Manach et al., 2004; Gollu ¨cke et al., 2008a). These compounds occur naturally in forms varying from simple phenolic acids to complex polymerized tannins. Because of their inherent instability, polyphenols undergo transformations in the presence of light, oxygen, and as a result of heat processing, storage, and extraction procedures (Lesschaeve and Noble, 2005; Gollu ¨cke et al., 2008b, 2009). For this reason, the daily consumption and dietary requirements for these compounds are difficult to measure. Although considered a powerful antioxidant, recently, new mechanisms for the physiological effects of polyphenols have been proposed. For example, modulation of gene expression, induction of apoptosis, decrease in platelet aggregation, increase in blood vessel dilation, modulation of intercellular signaling, modulation of enzyme activities associated with carcinogen activation, and detoxification and chelation of transition metals, such as iron (Duthie et al., 2000; Andrade et al., 2006). c 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 0959-8278
European Journal of Cancer Prevention 2012, 00:000–000 Keywords: chemoprevention, oral cancer, polyphenol Departments of aPathology, bBiosciences, Federal University of Sa˜o Paulo, UNIFESP and cHEXALAB and Department of Nutrition, Catholic University of Santos, Sa˜o Paulo, Brazil Correspondence to Daniel A. Ribeiro, DDS, PhD, Department of Biosciences, Av, Ana Costa, 95, Vila Mathias, Santos, Sa˜o Paulo 11060-001, Brazil Tel: + 55 133 778 3774; fax: + 55 133 223 2592; e-mail: darib[email protected]
Received 31 August 2012 Accepted 11 October 2012
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supplements. Interestingly, green tea and soy, two of the most cited supplements, contain polyphenols as bioactive compounds that are defined as chemical substances that can exert direct action on a living organism, either preventing or even blocking human diseases such as cancer. Oral squamous cell carcinoma (SCC) is the most common head and neck cancer, and it often has a poor prognosis owing to local tumor invasion and frequent lymph node metastasis (Arenas-Huertero et al., 1999). The development of oral cancer is usually preceded by a premalignant phase, the most common of which is leukoplakia. Malignant transformation of these leukoplakias varies in different parts of the world, probably as a result of differences in tobacco and dietary habits, which ranges from 3 to 8.1% (Scheifele and Reichart, 2003). Although epithelial dysplasia is an important predictive factor of malignant transformation, not all dysplastic lesions will become malignant. The mechanisms involved in the transformation of premalignant/ potentially malignant lesions to invasive cancer are still largely unknown. Despite recent advances in therapy, the prognosis of patients with oral SCC has not improved significantly in recent decades (Xi and Grandis, 2003). It is desirable to examine the precise pathobiological mechanisms involved in oral tumorigenesis to identify reliable biomarkers for the prevention of oral SCCs. Chemoprevention is a promising approach for controlling cancer as a result of specific natural products or synthetic agents able to suppress, reverse, or even prevent premalignancy before transformation into invasive cancer. Probably, the use of polyphenols as a chemopreventive agent would be a suitable tool for modulating the oral carcinogenesis process. The aim of this article is to present data generated from the use of polyphenols as a chemopreventive agent in oral carcinogenesis using in-vitro and in-vivo test systems. Chemoprevention studies with polyphenols focusing oral carcinogenesis In-vitro studies
Dietary polyphenols, including flavonoids, have been associated with cancer-preventive properties. A total of 150 chemically defined natural and synthetic polyphenols (flavonoids, dibenzoylmethanes, dihydrostilbenes, dihydrophenanthrenes, and 3-phenylchromen-4-ones) were investigated for cytotoxic activity against normal, tumor, and HIVinfected cells. They showed higher cytotoxic activity against human oral SCC HSC-2 and salivary gland tumor HSG cell lines than against normal human gingival fibroblasts (HGF) (Fukai et al., 2000). The active components induced internucleosomal DNA fragmentation in human promyelocytic leukemic HL-60 cells, but not in HSC-2 cells. Most of the polyphenols failed to reduce the cytophathic effect of HIV infection in MT-4 cells (Fukai et al., 2000). The cytotoxicity of a green tea polyphenol (GTP) extract to cell lines derived from the human oral cavity was assessed. The sequence of sensitivity was carcinoma
HSC-2 cells > immortalized gingival GT1 fibroblasts > normal gingival HGF-2 fibroblasts (Babich et al., 2007). Apparently, a mode of cytotoxicity of the GTP extract, in particular to the carcinoma HSC-2 cells, was to induce oxidative stress, as by the generation of H(2)O(2), the depletion of intracellular glutathione in reduced state (GSH), the protection conferred by extracellular GSH, and cell hypersensitivity (Babich et al., 2007). Green tea and its constituents selectively induce apoptosis only in oral carcinoma cells, whereas GTP epigallocatechin-3 gallate (EGCG) was able to inhibit the growth and invasion of oral carcinoma cells (Babich et al., 2007). These differential responses to green tea and its constituents between normal and malignant cells were correlated with the induction of p57 (Hsu et al., 2001). Epithelial to mesenchymal transition plays a crucial role in the progression, invasion, and metastasis of epithelial tumorgenesis. Some authors have provided molecular evidence associated with the antimetastatic effect of EGCG in an oral squamous cell culture system by showing an almost complete inhibition on the invasion of SCC-9 cells through a reduced expression of matrix metalloproteinase-2 (MMP-2) and urokinasetype plasminogen activator (Chen et al., 2011). EGCG exerts an inhibitory effect on cell migration, motility, spread, and adhesion. These results suggested that EGCG could reduce the invasion and cell growth of tumor cells, and such a characteristic may be very valuable in developing a potential cancer therapy (Chen et al., 2011). On pretreatment of SCC-9 cells with benzo(a)pyrene, it was found that two of the more common unmethylated polyphenols, curcumin and quercetin, were potent inhibitors (Walle and Walle, 2007). Quercetin also induced dose-dependent and time-dependent, irreversible inhibition of cell growth and cellular DNA synthesis on SCC-9 cells (Haghiac and Walle, 2005). Some remarkable differences were observed in the morphology and membrane integrity of cells after quercetin treatment (Haghiac and Walle, 2005). Interestingly, quercetin induced necrosis at 24 and 48 h, whereas at 72 h, cells underwent apoptosis, correlating with the activation of caspase-3 (Haghiac and Walle, 2005). Prolonged exposure of the surviving cells to quercetin causes apoptosis, presumably mediated by inhibition of TS protein (Haghiac and Walle, 2005). Resveratrol induced significant dose-dependent inhibition in cell growth as well as in DNA synthesis (ElAttar and Virji, 1999). Quercetin exerted a biphasic effect, stimulation at 1 and 10 mmol/l, and minimal inhibition at 100 mmol/l in cell growth and DNA synthesis. The combination of resveratrol with quercetin resulted in a gradual and significant increase in the inhibitory effect of quercetin on cell growth and DNA synthesis (ElAttar and Virji, 1999). By contrast, resveratrol had no effect on CYP1B1 in the SCC-9 cells (Wen and Walle, 2005). Hsu et al. (2005) found that EGCG upregulates p21WAF1 in the oral carcinoma cell line, OSC2. The current study
Polyphenols in oral carcinogenesis de Moura et al.
determined the impact of siRNA-suppressed p21WAF1 and its response to EGCG on cell growth, DNA synthesis, and apoptosis (Hsu et al., 2005). Taken as a whole, these findings suggest that p21WAF1 is involved in EGCGinduced growth arrest of OSC2 cells, which may facilitate caspase 3-mediated apoptosis. Thus, the expression of functional p21WAF1 may promote phytochemicalmediated growth arrest and apoptosis in oral carcinoma cells (Hsu et al., 2005). EGCG could induce p57 in normal keratinocytes in a dose-dependent and time-dependent manner, whereas the levels of p57 protein in cell lines SCC25 and OSC2 were unaltered. The differential response in p57 induction was consistent with the apoptosis status. The data suggest that the chemopreventive effects of GTPs may involve p57-mediated cell cycle regulation in normal epithelial cells (Hsu et al., 2001). EGCG, epicatechin-3-gallate (ECG), and (–)epigallocatechin (EGC) induced significant dose-dependent inhibition in cell growth (Elattar and Virji, 2000). In the DNA study, the three compounds exerted a stimulatory effect, followed by a significant dose-dependent inhibitory effect (Elattar and Virji, 2000). Dosedependent changes in cell morphology were also observed after cell treatment with EGCG (Elattar and Virji, 2000). Using HSC-2 carcinoma cells, ECG, catechin gallate, and EGCG were classified as highly toxic, EGC as moderately toxic, and catechin C and epicatechin as least toxic (Babich et al., 2005). The cytotoxicity of ECG was unaffected by a metabolic activating system by means of a hepatic microsomal S-9 mix (Babich et al., 2005). ECG also induced apoptosis in the carcinoma HSC-2 cells, but not in the normal HGF-2 fibroblasts (Babich et al., 2005). This research supports those studies suggesting that tea green is an effective chemopreventive agent against oral carcinoma cells (Babich et al., 2005). Accumulating evidence suggests that RECK is a tumor suppressor gene that negatively regulates MMPs and inhibits tumor invasion, angiogenesis, and metastasis. Kato et al. (2008) examined the effects of EGCG on the methylation status of the RECK gene and cancer invasion in oral SCC cell lines. The results showed that treatment of oral cancer cells with EGCG partially reversed the hypermethylation status of the RECK gene and significantly enhanced the expression level of RECK mRNA. Inhibition of MMP-2 and MMP-9 levels was also observed by the authors after treatment with EGCG (Kato et al., 2008). EGCG potently induces p57 in normal human primary epidermal keratinocytes, but not in epithelial cancer cells (Yamamoto et al., 2007). In humans, reduced expression of p57 is associated with advanced tumors, and tumor cells with inactivated p57 undergo apoptosis when exposed to EGCG (Yamamoto et al., 2007). In normal human primary epidermal keratinocytes, EGCGinduces p57 through the p38 mitogen-activated protein kinase signaling pathway (Yamamoto et al., 2007). In p57negative tumor cells, c-Jun N-terminal kinase signaling
mediates EGCG-induced apoptosis, and exogenous expression of p57 suppresses EGCG-induced apoptosis through the inhibition of c-Jun N-terminal kinase (Yamamoto et al., 2007). The restoration of p57 expression in tumor cells significantly reduced tumorigenicity in athymic mice (27/0). On treatment of HSC-2 cells and normal GN46 fibroblasts with theaflavin-3,30 -digallate (TF-3), a polyphenol in black tea, a concentration-dependent and time-dependent inhibition of growth was observed, with the tumor cells more sensitive than the fibroblasts (Schuck et al., 2008). TF-3 generated reactive oxygen species, hydrogen peroxide and superoxide, respectively, suggesting that TF-3 may be an inducer of oxidative stress (Schuck et al., 2008). Apoptosis was not observed in GN46 fibroblasts treated with TF-3 (Schuck et al., 2008). The combination with bovine milk lactoferrin (bLF) on human tongue squamous carcinoma (CAL-27) and HGF cells was also evaluated (Mohan et al., 2007). Both green (Polyphenon-E; P-E) and black tea polyphenols (Polyphenon-B; P-B) preferentially inhibit the growth of CAL-27 cells in a dose-dependent manner (Mohan et al., 2007). Analysis of the mechanism showed nuclear fragmentation and condensation with the appearance of the A(o) peak indicative of apoptosis. Furthermore, tea polyphenols transduced the apoptosis signal through generation of reactive oxygen species and a decrease in the Bcl-2/Bax ratio, thereby inducing mitochondrial permeability transition with the consequent activation of caspase-3 (Mohan et al., 2007). To further elucidate the role of tea flavonoids in antitopoisomerase activity in terms of inhibition of cell proliferation, some authors have examined the capacity of the phenolic content of Yerba mate tea products (MT) (Ilex paraguariensis) in oral carcinoma cell proliferation (Gonzalez de Mejia et al., 2005). Higher anti-topoisomerase II activity was observed against the JN394t(2–4) strain for Nobleza Gaucha MT (IC50 = 0.43mg equiv of CH) in comparison with GA (IC50 = 112 mmol/l) and CH (IC50 > 1500 mmol/l). MT showed catalytic anti-topoisomerase activity against Topo II, but not against Topo I. In addition, MT showed dosedependent cytotoxicity against all squamous cell lines tested. It can be concluded that MT is rich in phenolic constituents and can also inhibit oral cancer proliferation (Gonzalez de Mejia et al., 2005). In-vivo studies
To the best of our knowledge, there are few studies showing the chemopreventive activities of polyphenols following oral carcinogenesis in vivo, particularly in humans. The approach is very important because in-vitro test systems do not consider the complex homeostatic situation that occurs in vivo. Some authors have examined the effect GTP on the activities of cytochrome b5, cytochrome P450, cytochrome b5 reductase, cytochrome P450 reductase, arryl hydrocarbon hydroxylase, DT-diaphorase (phase I enzymes), and
4 European Journal of Cancer Prevention 2012, Vol 00 No 00
glutathione-S-transferase and UDP-glucuronyl transferase (phase II enzymes) following rat tongue carcinogenesis by 4-nitroquinoline 1-oxide. On supplementation of GTP by both simultaneous and post-treatment mode, there was a significant increase in the activity of glutathioneS-transferase and UDP-glucuronyl transferase and a significant decrease in the activity of phase I enzymes. There was a significant decrease in the number of tumors, tumor volume, and oral SCC in both simultaneous and postGTP-treated animals. Comparing simultaneous and postGTP-treated animals the number of tumors, tumor volume and oral SCC were significantly reduced in post-treated animals (Srinivasan et al., 2008). These findings are in agreement with a previous study carried out by the same research group suggesting a moderate increase in the levels of GSH, protein free thiols and total thiols and a decrease in the levels of GSSG, conjugated dienes, and the activity of g-glutamyl-transferase (Srinivasan et al., 2004). Thus, GTP reduces the oxidant production, and thereby maintains the endogenous low-molecular-weight cellular thiols in experimentally oral cancer-induced rats (Srinivasan et al., 2004).
Combination chemoprevention using tea polyphenols as one of the components has received growing attention in recent years. In this respect, some authors have designed a study to evaluate the antiproliferative and apoptosisinducing effects of a combination of bLF and black tea polyphenol (Polyphenon-B: P-B) on 7,12-dimethylbenz(a)anthracene-induced hamster buccal pouch carcinogenesis (Chandra Mohan et al., 2006). Although the dietary administration of bLF and Polyphenon-B alone significantly reduced the incidence of tumor, combined administration of bLF and Polyphenon-B was more effective in inhibiting hamster buccal pouch carcinogenesis by restoring normal cytokeratin expression, inhibiting cell proliferation, and inducing apoptosis (Li et al., 1999). When the preventive effects of green tea, tea pigments, and mixed tea (a composite of whole water extract of green tea, tea polyphenols, and tea pigments) on 7,12-dimethylbenz(a)anthracene-induced oral carcinogenesis in golden Syrian hamsters were studied, the results showed that oral administration of 1.5% green tea, 0.1% tea pigments, and 0.5% mixed tea as the sole source of drinking water
Chemopreventive studies from polyphenols against oral carcinogenesis in chronological order
Experimental test used
Human oral squamous cell carcinoma
Resveratrol and quercetin
Black tea polyphenols
Human oral squamous cell carcinoma and salivary gland tumor Human oral squamous cell carcinoma Human keratinocytes and oral squamous cell carcinoma Rat
In vitro In vitro In vitro
Natural and synthetic polyphenols with molecular weights ranging from 224 to 824 Epigallocatechin-3 gallate and catechin gallate Green tea polyphenols
Green tea polyphenols 0
Human oral squamous cell carcinoma
Human oral squamous cell carcinoma Human oral squamous cell carcinoma Human oral squamous cell carcinoma
In vitro In vitro In vitro
5,7-Dimethoxyflavone, 3 ,4 -dimethoxyflavone and resveratrol Epigallocatechin-3 gallate Epigallocatechin-3 gallate and catechin gallate Mate tea products
Human oral squamous cell carcinoma
Curcumin and quercetin
Head and neck cancer
Black tea polyphenols
Human oral cell lines Normal fibroblast and oral squamous cell carcinoma Human oral squamous cell carcinoma
In vitro In vitro In vitro
Catechin gallate Green (Polyphenon-E; P-E) and black tea polyphenols (Polyphenon-B; P-B) Curcumin and quercetin
Normal human primary epidermal keratinocytes and epithelial cancer cells Normal fibroblasts and oral squamous cell carcinoma Rat
Green tea polyphenols
Human oral squamous cell carcinoma
Human oral squamous cell carcinoma
Main findings Inhibition of cell growth, ElAttar and Virji (1999) Modulation of carcinogenesis, inhibiting cell proliferation and inducing apoptosis, Li et al. (1999) DNA fragmentation, Fukai et al. (2000) Inhibition in cell growth, Elattar and Virji (2000) Increased p57 expression, Hsu et al. 2001 Positive antioxidant activity, Srinivasan et al. (2004) Inhibition of CYP1B1/1A1 function, Wen and Walle (2005) Upregulation of p21WAF1, Hsu et al. 2005 Positive cytotoxicity, Babich et al. (2005) Catalytic anti-topoisomerase activity and positive cytotoxicity, Gonzalez de Mejia et al. (2005) Inhibition of cell growth and cellular DNA synthesis, Haghiac and Walle (2005) Inhibition of tumor growth and induction of apoptosis, Wolter et al. (2006) Reduced incidence of tumor, Chandra Mohan et al. (2006) Positive cytotoxicity, Babich et al. (2007) Inhibition of cell growth, Mohan, et al. (2007) Inhibition of benzo[a]pyrene induced cellular damage, Walle and Walle (2007) Increased p57 expression, Yamamoto et al. (2007) Inhibition of tumor growth, Schuck et al. (2008) Increase in the activity of GST and UDP-GT, Srinivasan et al. (2008) Altered hypermethylation of the RECK gene, Schuck et al. (2008) Inhibitory effect on cell migration, motility, spread, and adhesion, Chen et al. (2011)
Polyphenols in oral carcinogenesis de Moura et al.
significantly reduced the mean tumor burden and the incidence of dysplasia and oral carcinoma (Li et al., 1999). The frequency of micronucleated cells, the number of AgNOR, the total volume of AgNORs, the labeling index of proliferating cell nuclear antigen, and the level of epidermal growth factor receptor expression in the oral mucosal cells were also significantly reduced (Li et al., 1999). Resistance to chemotherapy is a common problem encountered in the treatment of head and neck squamous cell carcinoma (HNSCC). Chemoresistant HNSCC tumors frequently overexpress antiapoptotic proteins, such as Bclx(L). (–)-gossypol, the negative enantiomer of a cottonseed polyphenol, binds to Bcl-x(L) and has recently been shown to inhibit HNSCC proliferation in vitro (35). The assay was assessed using two human HNSCC cell lines with high Bcl-x(L) expression levels. The mitotic rate in tumors from (–)-gossypol-treated animals was significantly lower than that in controls, and an increase in the percentage of apoptotic cells was observed in treated tumors (Wolter et al., 2006). Residual tumors remained growth-suppressed for 2 weeks after the cessation of (–)-gossypol treatment. It seems that (–)-gossypol can inhibit tumor growth in the HNSCC cell lines (Wolter et al., 2006). All results are summarized in Table 1. Concluding remarks
In this article, we have reported recent studies focusing on the chemopreventive properties of polyphenols against oral carcinogenesis using in-vitro and in-vivo test systems. Although these data have yielded important biomarkers for understanding the mechanisms of action induced by polyphenol on eukaryotic cells, either ordinary or tumor cells, much remains to be examined. More adequately powered, randomized, placebo-controlled human studies as well as animal studies are required on polyphenols for a better understanding of the role of this xenobiotic specifically in oral cells. In addition, there are a large number of structurally different polyphenols that are relevant for health, and obtaining enough information to set a dietary reference intake for each of these will not be feasible in the foreseeable future (Williamson and Holst, 2008). Therefore, this area warrants further investigation as a new way of thinking, which would apply not only to polyphenols but also to other phytochemicals used as promising therapeutic agents against oral human diseases.
Acknowledgements This work was supported by CNPq (Conselho Nacional de Desenvolvimento Cientı´fico e Tecnolo´gico) and CAPES (Coordenac¸˜ao de Aperfeic¸oamento de Pessoal de Nı´vel Superior). D.A.R. is a recipient of the CNPq fellowship. Conflicts of interest
There are no conflicts of interest.
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