3,3'-Diindolylmethane Exhibits Significant Metabolism after Oral Dosing in Humans.

3,3'-Diindolylmethane (DIM), a major phytochemical derived from ingestion of cruciferous vegetables, is also a dietary supplement. In preclinical models, DIM is an effective cancer chemopreventive agent and has been studied in a number of clinical trials. Previous pharmacokinetic studies in preclinical and clinical models have not reported DIM metabolites in plasma or urine after oral dosing, and the pharmacological actions of DIM on target tissues is assumed to be solely via the parent compound. Seven subjects (6 males and 1 female) ranging from 26-65 years of age, on a cruciferous vegetable-restricted diet prior to and during the study, took 2 BioResponse DIM 150-mg capsules (45.3 mg DIM/capsule) every evening for one week with a final dose the morning of the first blood draw. A complete time course was performed with plasma and urine collected over 48 hours and analyzed by UPLC-MS/MS. In addition to parent DIM, two monohydroxylated metabolites and 1 dihydroxylated metabolite, along with their sulfate and glucuronide conjugates, were present in both plasma and urine. Results reported here are indicative of significant phase 1 and phase 2 metabolism and differ from previous pharmacokinetic studies in rodents and humans, which reported only parent DIM present after oral administration. 3-((1H-indole-3-yl)methyl)indolin-2-one, identified as one of the monohydroxylated products, exhibited greater potency and efficacy as an aryl hydrocarbon receptor agonist when tested in a xenobiotic response element-luciferase reporter assay using Hepa1 cells. In addition to competitive phytochemical-drug adverse reactions, additional metabolites may exhibit pharmacological activity highlighting the importance of further characterization of DIM metabolism in humans. SIGNIFICANCE STATEMENT: 3,3'-Diindolylmethane (DIM), derived from indole-3-carbinol in cruciferous vegetables, is an effective cancer chemopreventive agent in preclinical models and a popular dietary supplement currently in clinical trials. Pharmacokinetic studies to date have found little or no metabolites of DIM in plasma or urine. In marked contrast, we demonstrate rapid appearance of mono- and dihydroxylated metabolites in human plasma and urine as well as their sulfate and glucuronide conjugates. The 3-((1H-indole-3-yl)methyl)indolin-2-one metabolite exhibited significant aryl hydrocarbon receptor agonist activity, emphasizing the need for further characterization of the pharmacological properties of DIM metabolites.

Implications of Withaferin-A for triple-negative breast cancer chemoprevention.

Triple-negative breast cancer (TNBC) accounts for about 15 % of all breast cancer cases, and unlike other malignancies, it lacks definite prognostic markers. While improved survival responses have been documented with the ongoing therapeutic approaches, the development of tumor resistance mechanisms to these treatment options pose major challenges in the treatment of TNBC. Notably, naturally occurring medicinal compounds have been studied extensively for their anti-neoplastic activities in cancer models including breast cancer due to their safe and non-deleterious effects. Among various dietary compounds, Withaferin-A (WA), a phytochemical derived from an ayurvedic medicinal plant, Withania somnifera has been characterized to possess anti-inflammatory and anti-cancer properties. Importantly, multiple studies have shown that WA exhibits promising anti-tumoral activities against in-vitro and in-vivo experimental models of TNBC and that its combination has been documented to enhance chemotherapy efficacy. The current review highlights the mechanistic insights with recent updates including the pharmacokinetics parameters and implications of WA against breast cancer with major emphasis on TNBC.

Dietary Phenolics against Breast Cancer. A Critical Evidence-Based Review and Future Perspectives.

Breast cancer (BC) is the most common malignancy and the leading cause of cancer-related death in adult women worldwide. Over 85% of BC cases are non-hereditary, caused by modifiable extrinsic factors related to lifestyle, including dietary habits, which play a crucial role in cancer prevention. Although many epidemiological and observational studies have inversely correlated the fruit and vegetable consumption with the BC incidence, the involvement of their phenolic content in this correlation remains contradictory. During decades, wrong approaches that did not consider the bioavailability, metabolism, and breast tissue distribution of dietary phenolics persist behind the large currently existing gap between preclinical and clinical research. In the present review, we provide comprehensive preclinical and clinical evidence according to physiologically relevant in vitro and in vivo studies. Some dietary phenolics such as resveratrol (RSV), quercetin, isoflavones, epigallocatechin gallate (EGCG), lignans, and curcumin are gaining attention for their chemopreventive properties in preclinical research. However, the clinical evidence of dietary phenolics as BC chemopreventive compounds is still inconclusive. Therefore, the only way to validate promising preclinical results is to conduct clinical trials in BC patients. In this regard, future perspectives on dietary phenolics and BC research are also critically discussed.

Resveratrol: An overview of its anti-cancer mechanisms.

Cancer is one of the leading causes of death worldwide. Chemotherapy and radiotherapy are the conventional primary treatments for cancer patients. However, most of cancer cells develop resistance to both chemotherapy and radiotherapy after a period of treatment, besides their lethal side-effects. This motivated investigators to seek more effective alternatives with fewer side-effects. In the last few years, resveratrol, a natural polyphenolic phytoalexin, has attracted much attention due to its wide biological effects. In this concise review, we highlight the role of resveratrol in the prevention and therapy of cancer with particular focus on colorectal and skin cancer. Also, we discuss the molecular mechanisms underlying its chemopreventive and therapeutic activity. Finally, we highlight the problems associated with the clinical application of resveratrol and how attempts have been made to overcome these drawbacks.

Piperine as a Potential Anti-cancer Agent: A Review on Preclinical Studies.

Recently many studies showed anticancer activities of piperine, a pungent alkaloid found in black pepper and some other Piper species. We attempted to summarize acquired data that support anticancer potential of this natural agent. Piperine has been reported to possess effective chemopreventive activity. It has been studied to affect via several mechanisms of action, in brief enhancing antioxidant system, increasing level and activity of detoxifying enzymes and suppressing stem cell self-renewal. Moreover, piperine has been found to inhibit proliferation and survival of various cancerous cell lines via modulating cell cycle progression and exhibiting anti-apoptotic activity, respectively. This compound has been shown to modify activity of various enzymes and transcription factors to inhibit invasion, metastasis and angiogenesis. Interestingly, piperine has exhibited antimutagenic activity and also inhibited activity and expression of multidrug resistance transporters such as P-gp and MRP-1. Besides, about all reviewed studies have reported selective cytotoxic activity of piperine on cancerous cells in compared with normal cells. Altogether, the studies completely underline promising candidacy of piperine for further development. The collected preclinical data we provided in this article can be useful in the design of future researches especially clinical trials with piperine.

Chemoprevention of Breast Cancer by Transdermal Delivery of α-Santalol through Breast Skin and Mammary Papilla (Nipple).

PURPOSE: Almost all breast cancers originate from epithelial cells lining the milk ducts in the breast. To this end, the study investigated the feasibility of localized transdermal delivery of α-santalol, a natural chemopreventive agent to the breast. METHODS: Different α-santalol formulations (cream, solution and microemulsion) were developed and the in vitro permeability was studied using excised animal (porcine and rat) and human breast skin/mammary papilla (nipple). The in vivo biodistribution and efficacy studies were conducted in female rats. A chemical carcinogenesis model of breast cancer was used for the efficacy studies. RESULTS: Phospholipid based α-santalol microemulsion showed the highest penetration through the nipple and breast skin. Delivery of α-santalol through the entire breast (breast skin and nipple) in vivo in rats resulted in significantly higher concentration in the mammary gland compared to transdermal delivery through the breast skin or nipple. There was no measurable α-santalol concentration in the blood. Transdermal delivery of α-santalol reduced the tumor incidence and tumor multiplicity. Furthermore, the tumor size was significantly reduced with α-santalol treatment. CONCLUSIONS: The findings from this study demonstrate the feasibility of localized transdermal delivery of α-santalol for chemoprevention of breast cancer.

A Presurgical Study of Lecithin Formulation of Green Tea Extract in Women with Early Breast Cancer.

Epidemiologic data support an inverse association between green tea intake and breast cancer risk. Greenselect Phytosome (GSP) is a lecithin formulation of a caffeine-free green tea catechin extract. The purpose of the study was to determine the tissue distribution of epigallocatechin-3-O-gallate (EGCG) and its effect on cell proliferation and circulating biomarkers in breast cancer patients. Twelve early breast cancer patients received GSP 300 mg, equivalent to 44.9 mg of EGCG, daily for 4 weeks prior to surgery. The EGCG levels were measured before (free) and after (total) enzymatic hydrolysis by HPLC-MS/MS in plasma, urine, breast cancer tissue, and surrounding normal breast tissue. Fasting blood samples were taken at baseline, before the last administration, and 2 hours later. Repeated administration of GSP achieved levels of total EGCG ranging from 17 to 121 ng/mL in plasma. Despite a high between-subject variability, total EGCG was detectable in all tumor tissue samples collected up to 8 ng/g. Median total EGCG concentration was higher in the tumor as compared with the adjacent normal tissue (3.18 ng/g vs. 0 ng/g, P = 0.02). Free EGCG concentrations ranged from 8 to 65.8 ng/mL in plasma (P between last administration and 2 hours after <0.001). Free EGCG plasma levels showed a significant positive correlation with the Ki-67 decrease in tumor tissue (P = 0.02). No change in any other biomarkers was noted, except for a slight increase in testosterone levels after treatment. Oral GSP increases bioavailability of EGCG, which is detectable in breast tumor tissue and is associated with antiproliferative effects on breast cancer tissue. Cancer Prev Res; 10(6); 363-9. ©2017 AACR.

Anticarcinogenic Effects of α-Mangostin: A Review.

Cancer chemoprevention is a promising strategy taken to block, reverse, or retard carcinogenesis. α-Mangostin, a natural xanthone isolated from the pericarps of mangosteen, represents one of the most studied chemopreventive agents. This compound has been reported to interfere with all the major stages of carcinogenesis: initiation, promotion, and progression. A number of mechanisms have been proposed for its anticarcinogenic activities. This review summarizes the current knowledge on the mechanisms that contribute to the observed activity of α-mangostin related to (i) modulation of carcinogenic biotransformation and mitigation of oxidative damage, (ii) induction of growth arrest and apoptosis, (iii) suppression of angiogenesis and metastasis, and (iv) combination with clinical chemotherapy drugs enhancing their efficacy and decreasing the toxic side effects. In addition, pharmacokinetic and toxicological studies of α-mangostin have also been highlighted in this review. Despite an overwhelming amount of knowledge in preclinical studies, there was almost no translation of α-mangostin into the clinic. It is hoped that continuous extensive and profound research will lead to the application of α-mangostin from experimental studies to evidence-based, clinically applicable pharmacotherapy.

Bringing Curcumin to the Clinic in Cancer Prevention: a Review of Strategies to Enhance Bioavailability and Efficacy.

Curcumin is widely available, inexpensive spice that has been used in ancient folk medicine for millennia, especially in India. Curcumin has the pharmacological properties that slow or reverse cellular proliferation and enhance apoptosis and differentiation associated with a diverse array of molecular effects. Despite its effective anticarcinogenesis properties, curcumin's poor solubility, instability, and extensive metabolism result in poor oral bioavailability. Strategies to enhance curcumin delivery include encapsulating or incorporating curcumin in a nanoparticle or microparticle drug delivery system, synthesizing more stable curcumin analogs that resist metabolism while retaining curcumin's pharmacological properties, and adding another natural product that has bioenhancing properties to curcumin or combination of two of these strategies. This review comprehensively explores curcumin's chemistry and pharmacology followed by comparing and contrasting a vast number of strategies designed to enhance curcumin's bioavailability and its therapeutic effects. The review provides insights into which curcumin formulation strategies have the greatest promise to reach clinical application.

Sulforaphane Bioavailability and Chemopreventive Activity in Women Scheduled for Breast Biopsy.

Epidemiologic studies suggest a protective effect of cruciferous vegetables on breast cancer. Sulforaphane (SFN), an active food component derived from crucifers, has been shown to be effective in breast cancer chemoprevention. This study evaluated the chemopreventive effect of SFN on selective biomarkers from blood and breast tissues. In a 2- to 8-week double-blinded, randomized controlled trial, 54 women with abnormal mammograms and scheduled for breast biopsy were randomized to consume a placebo or a glucoraphanin (GFN) supplement providing SFN (n = 27). Plasma and urinary SFN metabolites, peripheral blood mononuclear cell (PBMC) histone deacetylase (HDAC) activity, and tissue biomarkers (H3K18ac, H3K9ac, HDAC3, HDAC6, Ki-67, p21) were measured before and after the intervention in benign, ductal carcinoma in situ, or invasive ductal carcinoma breast tissues. Within the supplement group, Ki-67 (P = 0.003) and HDAC3 (P = 0.044) levels significantly decreased in benign tissue. Pre-to-postintervention changes in these biomarkers were not significantly different between treatment groups after multiple comparison adjustment. GFN supplementation was associated with a significant decrease in PBMC HDAC activity (P = 0.04). No significant associations were observed between SFN and examined tissue biomarkers when comparing treatment groups. This study provides evidence that GFN supplementation for a few weeks is safe but may not be sufficient for producing changes in breast tissue tumor biomarkers. Future studies employing larger sample sizes should evaluate alternative dosing and duration regimens to inform dietary SFN strategies in breast cancer chemoprevention.

Pine bark extracts: nutraceutical, pharmacological, and toxicological evaluation.

Proanthocyanidins are among the most abundant constituents in pine bark extracts (PBEs). This review summarizes medical research on PBEs from Pinus pinaster, Pinus radiata, Pinus massoniana, and other less well characterized species. The precise mechanisms of the important physiologic functions of PBE components remain to be elucidated, but there is evidently great potential for the identification and development of novel antioxidant, anti-inflammatory, cardiovascular, neuroprotective, and anticancer medicines. Although toxicological data for PBEs are limited, no serious adverse effects have been reported. PBEs, therefore, may have potential as nutraceuticals and pharmaceuticals and should be safe for use as food ingredients.

Absorption and chemopreventive targets of sulforaphane in humans following consumption of broccoli sprouts or a myrosinase-treated broccoli sprout extract.

SCOPE: Sulforaphane (SFN), an isothiocyanate derived from crucifers, has numerous health benefits. SFN bioavailability from dietary sources is a critical determinant of its efficacy in humans. A key factor in SFN absorption is the release of SFN from its glucosinolate precursor, glucoraphanin, by myrosinase. Dietary supplements are used in clinical trials to deliver consistent SFN doses, but myrosinase is often inactivated in available supplements. We evaluated SFN absorption from a myrosinase-treated broccoli sprout extract (BSE) and are the first to report effects of twice daily, oral dosing on SFN exposure in healthy adults. METHODS AND RESULTS: Subjects consumed fresh broccoli sprouts or the BSE, each providing 200 µmol SFN daily, as a single dose and as two 100-µmol doses taken 12 h apart. Using HPLC-MS/MS, we detected ∼3 x higher SFN metabolite levels in plasma and urine of sprout consumers, indicating enhanced SFN absorption from sprouts. Twelve-hour dosing retained higher plasma SFN metabolite levels at later time points than 24-hour dosing. No dose responses were observed for molecular targets of SFN (i.e. heme oxygenase-1, histone deacetylase activity, p21). CONCLUSION: We conclude that the dietary form and dosing schedule of SFN may impact SFN absorption and efficacy in human trials.

Lycopene - antioxidant with radioprotective and anticancer properties. A review.

UNLABELLED: Ionizing radiation may cause damage to living tissue by producing free radicals like reactive oxygen species (ROS). ROS can randomly react with lipids, proteins and nucleic acids of cell causing oxidative stress and damage in these macromolecules, leading to pathogenesis of chronic diseases and age related and also cancer. The first line of defense from the damaging effects of ROS is antioxidants, which convert the oxidants to less reactive species. Lycopene (LYC) is an acyclic isomer of beta-carotene. It synthesized by plants or autotrophic bacteria but not by animals. Red fruits and vegetables, including tomatoes, watermelons, pink grapefruits, apricots, pink guavas and papaya contain LYC. This carotenoid has very strong antioxidant properties. The many studies confirm that dietary supplementation with LYC reduces risk of cancers of many organs, but also retard the growth of the tumors. LYC has also chemopreventive effects against other diseases such as cardiovascular disease, osteoporosis, male infertility and inhibits the toxic action of other agents. Numerous in vitro and animal studies showed that LYC may provide protection against damages induced by ionizing radiation. It suggests that supplementation of LYC might be useful in diminishing of negative effect of cancer radiotherapy or in mitigating the effects of possible radiation accidents on human health. KEY WORDS: lycopene, antioxidants, anticarcinogenic agents, radioprotection.

Low prostate concentration of lycopene is associated with development of prostate cancer in patients with high-grade prostatic intraepithelial neoplasia.

Prostate cancer (PC) is a frequent male malignancy and represents the second most diagnosed cancer in men. Since pre-cancerous lesions, i.e., the high-grade prostatic intraepithelial neoplasia (HGPIN), can be detected years before progression to PC, early diagnosis and chemoprevention are targeted strategies to reduce PC rates. Animal studies have shown that lycopene, a carotenoid contained in tomatoes, is a promising candidate for the chemoprevention of PC. However, its efficacy in humans remains controversial. The present study aimed to investigate the relevance of plasma and prostate concentration of lycopene after a lycopene-enriched diet in patients diagnosed with HGPIN. Thirty-two patients diagnosed with HGPIN were administered a lycopene-enriched diet (20-25 mg/day of lycopene; through 30 g/day of triple concentrated tomato paste) for 6 months. A 6-month follow-up prostate biopsy assessed progression to PC. Patients were classified into three groups according to the histopathological features of the 6-month follow-up biopsy results: prostatitis; HGPIN and PC. PSA and plasma lycopene levels were measured before and after the dietary lycopene supplementation. Prostatic lycopene concentration was only assessed after the supplementation diet. Only prostatic lycopene concentration showed significant differences between the three groups (p = 0.03). Prostatic lycopene concentration below a 1 ng/mg threshold was associated with PC at 6-month follow-up biopsy (p = 0.003). We observed no overall benefits from a 6-month lycopene supplementation, as the rate of HGPIN progression to PC in our population (9/32, 28%) was similar to rates reported in the literature. Baseline PSA levels also showed no significant changes after a lycopene-enriched diet. Our findings point to prostatic lycopene concentration as a promising biomarker of PC. Further prospective longitudinal studies are needed to assess the prognostic role of prostatic lycopene in PC.

Polymeric implants for the delivery of green tea polyphenols.

Polymeric implants (millirods) have been tested for local delivery of chemotherapeutic agents in cancer treatment. Modeling of drug release profiles is critical as it may provide theoretical insights on rational implant design. In this study, a biodegradable poly (ε-caprolactone) (PCL) polymeric implant delivery system was tested to deliver green tea polyphenols (GTPs), both in vitro and in vivo. Factors including polymer compositions, supplements, drug loads, and surface area of implants were investigated. Our data showed that GTPs were released from PCL implants continuously for long durations, and drug load was the main determining factor of GTPs release. Furthermore, rates of in vitro release and in vivo release in the rat model followed similar kinetics for up to 16 months. A mathematical model was deduced and discussed. GTP implants have the potential to be used systemically and locally at the tumor site as an alternative strategy.

Exploring the effects of isothiocyanates on chemotherapeutic drugs.

INTRODUCTION: Chemoprevention has emerged as a promising strategy to reduce the risk and to control cancer. In this context, isothiocyanates (ITCs), found in abundance in the form of glucosinolates in cruciferous vegetables, have gained increasing consideration for their chemopreventive activity. ITCs exert their effects mainly by inducing carcinogen metabolism or by inhibiting tumor cell proliferation. AREAS COVERED: In recent years, novel combination treatments, by coupling chemopreventive agents and typical chemotherapeutics, have been exploited to increase the antitumor activities. The aim of this article is to examine the foremost studies carried out, so far, on the effects of dietary and synthetic ITCs on different signaling pathways involved in the pharmacokinetics and pharmacodynamics of chemotherapeutic agents, in order to enhance their effectiveness. EXPERT OPINION: Undoubtedly, the beneficial anticarcinogenic potential of ITCs, both singly and in combination, has emerged in in vitro and in vivo studies. However, only a few clinical trials have been carried out so far with ITCs, which try to better define both the pharmacokinetic and pharmacodynamic impacts in humans. More toxicological evaluations after long-term administration of ITCs in different species are required for the clinical development of ITCs as anticarcinogenic agents.

[Pharmacokinetics of genistein in urine of healthy volunteers].

In order to study the excretion of genistein (GEN) capsule, an estrogen drugs, in human, 30 healthy volunteers were selected and orally administered 50, 100, and 300 mg genistein in an parallel study. Genistein were determined in urine by LC-MS/MS and glucuronidated genistein (GENG) were indirectly determined with enzymatic hydrolysis in urine by LC-MS/MS, and the pharmacokinetic parameters were analyzed by DAS software (ver 2.0). The result showed that the concentrations of genistein in human urine were less than 1% of the GENG, and the cumulative excretion of GEN in 48 h were 0.037, 0.134, and 0.142 mg, separately, and the urinary excretion percentage were only 0.07%, 0.13%, and 0.05%, separately. But the cumulative excretion of GENG in 48 h was 5.3, 13.8, and 15.4 mg, separately, and the urinary excretion percentage were 10.6%, 13.8%, and 5.1%, separately, and the max urinary excretive rate was 0.4, 1.0, and 1.4 mg x h(-1), separately (tmax were 6 h). Studies showed that part of drug excreted through kidney in a form of GENG in human, and the cumulative urinary excretion and the maximum excretion rate of GENG showed a proportional increase conditioned with the dose in the range of 50-100 mg, but showed non-linear increase feature in 300 mg.

Gamma-tocopherol attenuates moderate but not severe colitis and suppresses moderate colitis-promoted colon tumorigenesis in mice.

Inflammation can promote colon cancer. Mechanistic studies indicate that γ-tocopherol (γT), a major form of vitamin E in diets, has anti-inflammatory and anticancer properties. Here we investigated the effectiveness of γT and a mixture of tocopherols against colitis and colitis-promoted colon tumorigenesis in male BALB/c mice. γT or mixed tocopherols (at 0.1% diet) did not show any effect on colon tumorigenesis induced by azoxymethane (AOM, 10mg/kg) with three cycles of dextran sodium sulfate (DSS at 1.5-2.5%). γT failed to exhibit protection of severe colitis caused by three cycles of DSS at 2.5%. In contrast, when AOM-initiated carcinogenesis was promoted by relatively mild colitis induced by one-cycle DSS (1.5%), γT, but not mixed tocopherols, suppressed total multiplicity of macroscopic adenomas (P=0.06) and large adenomatous polyps (>2mm(2), P<0.05) by 60 and 85%, respectively. γT also significantly decreased tumor multiplicity (>2mm(2)) induced by AOM with two cycles of 1.5% DSS even when dietary supplementation was started after AOM injection. Consistently, γT but not mixed tocopherols attenuated DSS (1.5%)-induced colon inflammation and damage as well as formation of atypical glandular hyperplasia. Mice supplemented with tocopherols had high fecal excretion of 13'-carboxychromanol, a long-chain vitamin E metabolite shown to have potent anti-inflammatory activities. Our study demonstrates that γT is able to alleviate moderate but not severe colitis and its promoted tumorigenesis, and indicates that inflammation severity should be considered in evaluating anticancer effectiveness of chemoprevention agents.

Biological activities and bioavailability of mangosteen xanthones: a critical review of the current evidence.

Mangosteen (Garcinia mangostana L.) is a tropical tree native to Southeast Asia that produces a fruit whose pericarp contains a family of tricyclic isoprenylated polyphenols referred to as xanthones. Numerous in vitro studies have shown that these xanthones possess anti-oxidant, anti-proliferative, pro-apoptotic, anti-inflammatory and anti-carcinogenic activities. Aggressive marketing of such health promoting benefits has resulted in mangosteen's classification as a "superfruit". This has led to sales of mangosteen containing beverages in USA alone exceeding $200 million in 2008 despite very limited animal and human studies. This review will (a) critically address recent reports of in vivo studies on the bioavailability and metabolism of mangosteen xanthones, (b) update the in vitro and in vivo data on anti-cancer and anti-inflammatory activities of mangosteen xanthones, and (c) suggest needed areas of inquiry regarding the absorption, metabolism and efficacy of mangosteen xanthones.

Chemopreventive potential of flavonoids in oral squamous cell carcinoma in human studies.

Evidence available from nutritional epidemiology has indicated an inverse association between regular consumption of fruits and vegetables and the risk of developing certain types of cancer. In turn, preclinical studies have attributed the health-promoting effects of plant foods to some groups of phytochemicals, by virtue of their many biological activities. In this survey, we briefly examine the chemopreventive potential of flavonoids and flavonoid-rich foods in human oral carcinogenesis. Despite the paucity of data from clinical trials and epidemiological studies, in comparison to in vitro/in vivo investigations, a high level of evidence has been reported for epigallocatechin gallate (EGCG) and anthocyanins. These flavonoids, abundant in green tea and black raspberries, respectively, represent promising chemopreventive agents in human oral cancer.