Catechin Mixture Research Articles

Abstract PR06: Effect of polyphenon E on progression to prostate cancer after diagnosis of high grade prostatic intraepithelial neoplasia

Abstract Importance: In recent years, several studies have suggested effectiveness of green tea catechins in prostate cancer (PCa) chemoprevention. With the exception of one trial from Italy, this has not been further tested in a randomized trial setting in high-risk men with atypical small acinar proliferation (ASAP) or high grade prostatic intraepithelial neoplasia (HGPIN). Objective: To determine whether the daily consumption of a standardized formulation of green tea catechins (Polyphenon E) supplement for 1 year reduces the rate of progression to PCa in men, diagnosed with HGPIN or ASAP. Additional objectives were to evaluate tolerance, lower urinary tract symptoms (LUTS) and quality of life (QOL). Design, setting and participants: A randomized, double-blinded trial was conducted from September 2008 to March 2014 at medical centers in the US targeting 97 men diagnosed HGPIN or ASAP, randomized to treatment (n=49) or control arm (n=48). Supplement or placebo was initiated within 3 months of initial biopsy and continued for 1 year. Intervention: Participants were block randomized by baseline diagnosis and study site to receive Polyphenon E (PolyE), a decaffeinated, standardized green tea catechin mixture, the main component of which is (−)-epigallocatechin-3-gallate (EGCG) at a dose of 400 mgs EGCG per day (200 mgs twice a day [BID]), or placebo. Main outcomes and measures: Rate of progression to PCa at one year in men treated with PolyE or placebo following diagnosis of HGPIN or ASAP; evaluation of tolerance, LUTS and QOL. Results: Overall, we did not observe a difference in the number of men who progressed to PCa in one year in the Poly E (4/49) arm compared to placebo arm(6/48). Secondary analyses of patients reaching a definitive endpoint revealed that among men with baseline diagnosis of HGPIN, a greater number progressed to ASAP or PCa in the placebo arm (10/25) compared to the PolyE arm (3/26; P<0.05). Interestingly, this result was largely driven by the fact that a significantly greater number of subjects with baseline HGPIN progressed to ASAP in the placebo arm (5/25) compared to men in the PolyE arm (0/26; P <0.05). In men with baseline diagnosis of ASAP, the rate of cancer diagnosis at the end of intervention were similar in both study arms. Men in the PolyE group treated for one year demonstrated a significant decrease in serum tPSA compared to those in the placebo group (-0.90 ng/mL;(95%CI:-1.67, -0.12; P<0.05). No significant differences in tolerance, LUTS or QOL were observed between the two groups. Conclusions and Relevance: Daily intake of a standardized, decaffeinated catechin mixture containing 400 mgs EGCG (200 mgs BID) for 1 year is well tolerated and appears to produce chemoprevention effects in the early stages (HGPIN to ASAP) of prostate carcinogenesis. These findings should be confirmed in a phase III clinical trial prior to recommending use in clinical settings. Trial Registration: Clinical Trials.gov Identifier: NCT00596011 Acknowledgement: The research study was funded by the National Institute of Health- National Cancer Institute R01 CA12060-01A1. We acknowledge the contributions of Anthony M. Neuger, Domenico Coppola, Binglin Yue, (Moffitt Cancer Center); Kyle Anderson (Minneapolis VA Medical Center, Minneapolis, MN); Eduard Trabulsi (Jefferson Medical College, Philadelphia, PA); Tajammul Fazili (Overton Brooks VA, Shreveport, LA); Edward Giovanucci (Harvard University); Gregory Zagaja (University of Chicago, Chicago, IL); Shahnjayla Connors (University of Washington, St. Louis, MO); Folake Odedina (University of Florida). External Data Monitoring Board: Omer Kucuk, (Emory University), Phyllis Bowen (Retired), and Steven Clinton (Ohio State University). Citation Format: Nagi B. Kumar, Julio Pow-Sang, Kathleen M. Egan, Philippe A. Spiess, Shohreh Dickinson, Raoul Salup, Mohamed Helal, Jerry McLarty, Christopher R. Williams, Fred Schreiber, Said Sebti, Aslam Kazi, Loveleen Kang, Gwen Quinn, Tiffany Smith, Karen Diaz, Ganna Chornokur, Theresa Crocker, Michael J. Schell. Effect of polyphenon E on progression to prostate cancer after diagnosis of high grade prostatic intraepithelial neoplasia. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr PR06.

Randomized, Placebo-Controlled Trial of Green Tea Catechins for Prostate Cancer Prevention.

Preclinical, epidemiologic, and prior clinical trial data suggest that green tea catechins (GTC) may reduce prostate cancer risk. We conducted a placebo-controlled, randomized clinical trial of Polyphenon E (PolyE), a proprietary mixture of GTCs, containing 400 mg (-)-epigallocatechin-3-gallate (EGCG) per day, in 97 men with high-grade prostatic intraepithelial neoplasia (HGPIN) and/or atypical small acinar proliferation (ASAP). The primary study endpoint was a comparison of the cumulative one-year prostate cancer rates on the two study arms. No differences in the number of prostate cancer cases were observed: 5 of 49 (PolyE) versus 9 of 48 (placebo), P = 0.25. A secondary endpoint comparing the cumulative rate of prostate cancer plus ASAP among men with HGPIN without ASAP at baseline, revealed a decrease in this composite endpoint: 3 of 26 (PolyE) versus 10 of 25 (placebo), P < 0.024. This finding was driven by a decrease in ASAP diagnoses on the Poly E (0/26) compared with the placebo arm (5/25). A decrease in serum prostate-specific antigen (PSA) was observed on the PolyE arm [-0.87 ng/mL; 95% confidence intervals (CI), -1.66 to -0.09]. Adverse events related to the study agent did not significantly differ between the two study groups. Daily intake of a standardized, decaffeinated catechin mixture containing 400 mg EGCG per day for 1 year accumulated in plasma and was well tolerated but did not reduce the likelihood of prostate cancer in men with baseline HGPIN or ASAP.

Abstract B67: Effect of polyphenon E on progression to prostate cancer after diagnosis of high-grade prostatic intraepithelial neoplasia or atypical small acinar proliferation in African American men

Abstract Importance: Studies suggest that green tea catechins are worthy of investigation for prostate cancer (PCa) chemoprevention. AAM diagnosed with HGPIN had significantly elevated PCa risk, compared to AAM without HGPIN (83.3% vs 6.9%, p=0.0001). However, to date, there are no chemoprevention trials with GTC targeting a substantial number of AAM diagnosed with HGPIN, who have an exceptional risk for progression to aggressive prostate cancer. Objective: To determine whether the daily consumption of a standardized formulation of green tea catechins (Polyphenon E) supplement for 1 year reduces the rate of progression to PCa in men diagnosed with HGPIN or ASAP with a specific focus on AAM. Additional objectives were to evaluate tolerance, lower urinary tract symptoms (LUTS) and quality of life (QOL). Design, setting and participants: A randomized, double-blinded trial was conducted from September 2008 to March 2014 at 3 medical centers in the US targeting 97 men (including 20 AAM) diagnosed HGPIN or ASAP, randomized to treatment (n=49) or placebo arm (n=48). Supplement or placebo was initiated within 6 months of initial biopsy and continued for 1 year. Intervention: Participants were block randomized by baseline diagnosis to receive Polyphenon E (PolyE), a decaffeinated, standardized green tea catechin mixture, the main component of which is (−)-epigallocatechin-3-gallate (EGCG) at a dose of 400 mgs EGCG per day (200 mgs twice a day [BID]), or placebo. Main outcomes and measures: Rate of progression to PCa at one year in men treated with PolyE or placebo following diagnosis of HGPIN or ASAP; evaluation of tolerance, LUTS and QOL. Results: Overall, we did not observe a difference in the number of men who progressed to PCa in one year in the Poly E (4/49) arm compared to placebo arm(6/48). Among men with baseline diagnosis of HGPIN, a significantly greater number of subjects progressed to ASAP in the placebo arm (5/25) compared to men in the GTC arm (0/26; P &amp;lt;0.05). Specifically evaluating the effect of GTC in 20 AAM in this trial, results reveal that 2/12 (17%) AAM progressed to PCa in the placebo arm compared to 0/8 (0%) AAM receiving GTC. In subjects with baseline diagnosis of HGPIN, 3/9 men progressed to ASAP or PCa compared to 0/6 the GTC arm with no safety concerns. Post treatment serum tPSA was reduced in AAM on GTC (2.8ng/ml) compared to placebo (5.6ng.ml). No significant differences in tolerance, LUTS or QOL were observed between the two groups. Conclusions and Relevance: Daily intake of a standardized, decaffeinated catechin mixture containing 400 mgs EGCG (200 mgs BID) for 1 year is well tolerated and appears to produce chemoprevention effects in the early stages (HGPIN to ASAP). Targeting earlier stages of disease using chemoprevention agents with a favorable safety profile to prevent progression to clinically evident aggressive PCa may be key to eliminating disparity in PCa morbidity and mortality in the exceptionally high risk population of AAM. These findings should be confirmed in a phase III clinical trial prior to recommending use in clinical settings. Trial Registration: Clinical Trials.gov Identifier: NCT00596011 Citation Format: Nagi KUMAR, Michael Schell, Ganna Chornokur, Cathy Phelan. Effect of polyphenon E on progression to prostate cancer after diagnosis of high-grade prostatic intraepithelial neoplasia or atypical small acinar proliferation in African American men. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B67.

Effects of EGCG content in green tea extract on pharmacokinetics, oxidative status and expression of inflammatory and apoptotic genes in the rat ocular tissues

Green tea extract (GTE) exerts antioxidative activities in ocular tissues of rats, but high levels of (−)-epigallocatechin gallate (EGCG) can induce oxidative stress. In this study, pharmacokinetics, diurnal variation of oxidative status, antioxidation and transcription factors changes in ocular tissues of rats were investigated. Rats were fed intragastrically with GTE and catechin mixtures containing different amounts of EGCG. Plasma and various ocular tissues were taken for pharmacokinetic analysis, oxidation marker testings and gene expression assays. Effects of EGCG on ocular oxidation status were assessed by 8-isoprostane level and reduced/oxidized glutathione ratio. Oxidation, inflammation and apoptosis regulations in retina were evaluated by real-time polymerase chain reaction. Epicatechin, epigallocatechin and EGCG were dominant in various ocular tissues except vitreous humor, where gallocatechin was predominant. Diurnal variation of oxidative status was found in some compartments. GTE caused oxidative stress increase in the plasma, aqueous humor, vitreous humor, cornea and retina but decrease in the lens and choroid–sclera. Catechins mixture containing half dose of EGCG lowered 8-isoprostane in the retina and lens. GTE treatment induced superoxide dismutase 1 and glutathione peroxidase-3 expressions but suppressed catalase in the retina. Our results reveal pro-oxidation of GTE with high EGCG content to the ocular tissues. Optimal EGCG level is needed for protection.

Inhibition of Fungal Aflatoxin B1 Biosynthesis by Diverse Botanically-Derived Polyphenols

Purpose: To identify and characterize the capacity of diverse botanically-derived polyphenols to inhibit aflatoxin B1 (AFB1) production by Aspergillus flavus.Methods: A tea-derived polyphenol mixture and numerous individual polyphenols were tested for their effects on A. flavus growth and AFB1 production. Fungal spores were cultured for 60 h with polyphenols (range 0 ‒ 1,000 μg/mL). The fungi were enumerated by hemocytometry, and AFB1 in culture supernatants was quantified by high-performance liquid chromatography (HPLC).Results: Neither the tea-derived polyphenol mixture nor individual polyphenol compound, except quercetin, inhibited A. flavus growth. Quercetin detectably inhibited growth at 800 μg/mL; none of the remaining polyphenols inhibited fungal proliferation, even at 1,000 μg/mL. However, catechin mixture and all individual polyphenols differentially inhibited fungal AFB1 biosynthesis. Non-ester catechin derivatives revealed stronger inhibitory activity than ester derivatives.Conclusion: Quercetin exhibits the strongest inhibitory effect on AFB1 production and is the only test compound that also inhibits fungal proliferation. Botanically-derived polyphenols are, therefore, promising reagents for controlling fungal contamination and associated toxic aflatoxin deposition in harvested crops and in food processing operations.Keywords: Polyphenols, Quercetin, Aflatoxin B1, Inhibition, Antioxidation

A gelatin based antioxidant enriched biomaterial by grafting and saturation: Towards sustained drug delivery from antioxidant matrix

Proteins grafted with antioxidant molecules have drawn much attention due to their increased life time and biocompatibility. When protein macromolecules are cross linked chemically and physically with antioxidant molecules, they can act as antioxidant biomaterials as well as scaffolds to release the antioxidant molecules by diffusion. In our work, we have attempted to release catechin molecules from the matrix of glutathione grafted gelatin. Conjugation of glutathione and cross linkage was done by carbodiimide method to achieve smaller pores in the gelatin matrix and the characterization was performed by means of FTIR-ATR and calorimetric analyses. The glutathione grafted gelatin (GGSH) has been shown to have more thermal stability and pores with lesser radii than blank gelatin (bGEL). Free radical scavenging activity of GGSH was also found to be more than that of bGEL. Catechin was added to GGSH and bGEL by physical blending in order to achieve short term release of antioxidant molecules. CD spectra revealed that significant conformational changes occurred in secondary structure of gelatin upon interaction with catechin. Slower rate of catechin release from GGSH reflected the influence of cross linkage and physical interactive forces on the drug release properties. We conclude that the mixture of catechin with GGSH can be a potent antioxidant biomaterial releasing catechin at slower rate than the mixture of catechin with bGEL.

Inhibition of Human Parainfluenza Virus Type 2 Growth in Vitro by Catechin is caused by the Inhibition of Genome and mRNA Syntheses and by the Disruption of Cytoskeleton, and that by Tannic Acid is Mainly Caused by Genome Synthesis Inhibition and the Disruption of Cytoskeleton

The antiviral activities of catechin mixture (catechin) and tannic acid against human parainfluenza virus type 2 (hPIV-2) were investigated in vitro. Catechin and tannic acid both inhibited cell fusion induced by hPIV-2 in LLCMK2 cells. However, high concentrations of them caused cell toxicity. Both catechin and tannic acid reduced the number of viruses released from the cells. Real time PCR showed that catechin almost completely inhibited virus genome RNA synthesis, and tannic acid largely inhibited it. Virus nucleoprotein (NP), fusion (F) and hemaggulutinin-neuraminidase (HN) gene syntheses were largely inhibited by catechin, and mRNA syntheses of these proteins were partly inhibited by catechin. However, tannic acid did not cause inhibition. An indirect immunofluorescence study showed that catechin partly inhibited virus NP, F and HN protein syntheses, but tannic acid did not inhibit either virus NP, F or HN protein syntheses. Using a recombinant green fluorescence protein (GFP)-expressing hPIV-2 without matrix protein (rhPIV-2∆MGFP), it was found that virus entry into the cells was not inhibited by catechin or tannic acid, and that spreading of virus to the adjacent cells was not blocked by them. Catechin and tannic acid disrupted both actin microfilaments and microtubules. These results indicated that the inhibitory effect of catechin was caused by the inhibitions of both viral genome RNA and mRNA syntheses, and by the disruption of actin microfilaments and microtubules. However, inhibition by tannic acid was mainly caused by vial genome synthesis inhibition and the disruption of cytoskeleton.

224 Synergic tumor growth suppression with carbohydrate-restriction diet and natural AMP-dependent protein kinase activators

Background: Calorie restriction (CR) or low-carbohydrate diet (LCD) can increase life-span in normal cells but inhibit carcinogenesis. Various AMPdependent protein kinase (AMPK) activating phytochemicals also have CR-mimetic anticancer properties. We investigated whether carbohydraterestriction diet and phytochemical supplementation induce synergic tumor suppression. Methods: We used a mixture of curcumin, quercetin, catechins and resveratrol extracts for natural AMPK-activating agent. Survival analysis was performed in B16F10 melanoma model after fed control diet, control diet with phytochemicals (MP formula), LCD, LCD with phytochemicals (LCDmp), moderate-carbohydrate diet (MCD), and MCD with phytochemicals (MCDmp). Tumor suppression mechanisms, especially alterations in energy-dependent signaling pathways, histone methylation, and global gene expression were investigated. We evaluated the role of SIRT1 under glucose-restriction condition with MTT assay. Diet-induced cancer prevention effects were analyzed in a transgenic liver cancer model. Results: In melanoma model, MP, LCD, or MCD intervention did not produce survival benefit but LCDmp and MCDmp interventions increased median survival time significantly (p < 0.05). Suppression of the IGF-1R/PI3K/Akt/mTOR signaling, activation of the AMPK/SIRT1/LKB1pathway and NF-kB suppression were the major tumor suppression mechanisms. MTT assay showed suppressed proliferation of the B16F10 and A375SM cells after treatment of SIRT1 activator under low-glucose condition. Alterations in histone methylation within Pten and FoxO3a were demonstrated in tumor tissues. In transgenic liver cancer model, the MCDmp and LCDmp groups showed fewer tumor nodules. Microarray analysis revealed increased PPARa with decreased IL-6 and NF-kB after MCDmp intervention, which could be the major cancer prevention mechanism. Conclusion: AMPK-activating phytochemicals exert synergic anti-cancer activities under low-carbohydrate condition, and SIRT1 induces tumor suppression.

Sulforaphane, quercetin and catechins complement each other in elimination of advanced pancreatic cancer by miR-let-7 induction and K-ras inhibition.

Pancreatic ductal adenocarcinoma (PDA) has the worst prognosis of all malignancies, and current therapeutic options do not target cancer stem cells (CSCs), which may be the reason for the extreme aggressiveness. The dietary agents sulforaphane and quercetin enriched e.g., in broccoli, and the main and best studied green tea catechin EGCG hold promise as anti-CSC agents in PDA. We examined the efficacy of additional catechins and the combination of these bioactive agents to stem cell features and miRNA signaling. Two established and one primary PDA cell line and non-malignant pancreatic ductal cells were used. Whereas each agent strongly inhibited colony formation, the catechins ECG and CG were more effective than EGCG. A mixture of green tea catechins (GTCs) significantly inhibited viability, migration, expression of MMP-2 and -9, ALDH1 activity, colony and spheroid formation and induced apoptosis, but the combination of GTCs with sulforaphane or quercetin was superior. Following treatment with bioactive agents, the expression of miR-let7-a was specifically induced in cancer cells but not in normal cells and it was associated with K-ras inhibition. These data demonstrate that sulforaphane, quercetin and GTC complement each other in inhibition of PDA progression by induction of miR-let7-a and inhibition of K-ras.

Effects of catechins on Agrobacterium-mediated genetic transformation of Camellia sinensis

In this study, recalcitrance of tea plant ( Camellia sinensis) to Agrobacterium-mediated genetic transformation was investigated with an emphasis on specialized compounds in tea. Chemical constituents in tea leaves and calli were extracted into liquid Luria–Bertani (LB) medium to determine their biological activities on Agrobacterium growth, virulence, and plant transformation efficiency. Compared to the control Agrobacterium grown in LB medium, tea leaf extract containing 6.5 mg mL−1 catechins resulted in an 84.6 % reduction of Agrobacterium growth, a 73–36 % suppression of expression for the six virulence (vir) genes, browning of infected tobacco explant wounds, and an absence of transient or stable transformation events. Tea callus extract, containing 0.22 mg mL−1 catechins, did not significantly affect Agrobacterium growth or tobacco transgenic hairy root generation, whereas it enhanced the expression of some vir genes. Treatment with authentic catechin mixtures (other than caffeine) dissolved in LB resulted in suppression of Agrobacterium growth, vir gene expression, and tobacco transformation efficiency. Our data suggest that catechins are the key active constituents in tea leaves. Transient transformation efficiencies of tea leaves were much lower than those of tobacco leaves as indicated by the GUS (β-glucuronidase) assay, probably a result of inhibition by the catechins present in tea leaves. Lower transformation efficiencies of tea calli suggested that additional plant factor(s) might also exert inhibitory effects on tea plant transformation. Agrobacterium rhizogenes ATCC 15834 induced transgenic roots from the tea explants with 15–20 % efficiency. Our data suggested catechins inhibition of tea gene transformation could be overcome by using optimized strains of Agrobacterium.

Application of active zein-based films with controlled release properties to control Listeria monocytogenes growth and lipid oxidation in fresh Kashar cheese

Abstract The antimicrobial and antioxidant potential of zein and zein–wax composite films having different release profiles for lysozyme and mixture of lysozyme, catechin and gallic acid were tested on cold-stored fresh Kashar cheese inoculated with Listeria monocytogenes ATCC 7644. All lysozyme containing films prevented the increase of L. monocytogenes counts in Kashar cheese for 8 weeks at 4 °C, but it was only the zein–wax composite films with sustained lysozyme-release rates which caused a significant reduction (− 0.4 decimals) in initial microbial load of inoculated cheese samples. The mixture of catechin and gallic acid improved the in vitro antimicrobial effect of films against L. monocytogenes, but showed no considerable antimicrobial effect in cheese. However, the films containing catechin and gallic acid were effective in preventing oxidative changes in cheese. This study showed the possibility of increasing safety and quality of fresh cheeses by use of active packaging employing natural antimicrobial compounds and controlled release technology. Industrial relevance There has been a growing interest to develop the functional properties of packaging materials and to obtain packed foods with better shelf-life and quality. Active packaging incorporating antimicrobials is one of the most promising areas since application of this method can improve safety of foods by inhibiting pathogenic bacteria or controlling spoilage flora by using minimum amounts of active compounds. Recently, health concerns of consumers and environmental problems related to plastics increased the popularity of using natural antimicrobial substances in edible films and coatings. This work employs a GRAS status natural antimicrobial lysozyme and zein a major by-product of rapidly growing oil and bioethanol industries which can form self-standing films, coatings or casings. The results of this study showed the possibility of using flexible antimicrobial and antioxidant films with controlled release properties in diary industry.

Catechins play key role in green tea extract–induced postprandial hypoglycemic potential in vitro

Green tea is often associated with glycemic control benefit. However, the available evidence is not conclusive. In this study, we systematically assessed the contribution of main green tea extract (GTE) ingredients to the inhibition of carbohydrate digestive enzyme and intestinal glucose transport, which are two intervention options for postprandial blood glucose control. A catechin mixture (CM) solution containing seven catechins and epigallocatechin gallate (EGCG) solution was prepared based on the contents of individual catechins in the GTE as determined by high-performance liquid chromatography. The inhibitory potency of GTE, CM, and EGCG on α-amylase or α-glucosidase was compared in cell-free system. GTE’s inhibitory potency was mainly attributed to catechins, among which, EGCG accounted for at least 80 % of the α-amylase inhibitory activity and 90 % of the α-glucosidase inhibitory activity of GTE. In addition, the fluorescence quenching of the digestive enzymes by EGCG revealed that the binding site of EGCG-α-amylase was 1.2, and that for EGCG-α-glucosidase to be 2.0. The inhibitory potency of GTE, CM, and EGCG on glucose transport was assessed in Caco-2 monolayer system. Under the simulated fasting state, there was significant difference between the test materials regarding inhibitory potency according to two-way ANOVA (P > 0.05). Under the simulated fed state, CM showed stronger inhibition than EGCG only at the highest test concentration (25.7 μg/mL), while no significant difference was observed between CM and the GTE. In conclusion, our results suggest that green tea’s postprandial hypoglycemic potential can be attributed to its catechins.

Polyphenol E Enhances the Antitumor Immune Response in Neuroblastoma by Inactivating Myeloid Suppressor Cells

Neuroblastoma is a rare childhood cancer whose high risk, metastatic form has a dismal outcome in spite of aggressive therapeutic interventions. The toxicity of drug treatments is a major problem in this pediatric setting. In this study, we investigated whether Polyphenon E, a clinical grade mixture of green tea catechins under evaluation in multiple clinical cancer trials run by the National Cancer Institute (Bethesda, MD), has anticancer activity in mouse models of neuroblastoma. We used three neuroblastoma models: (i) transgenic TH-MYCN mouse developing spontaneous neuroblastomas; (ii) nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice xenotransplanted with human SHSY5Y cells; and (iii) A/J mice transplanted with syngeneic Neuro 2A cells. Mice were randomized in control and Polyphenon E-drinking groups. Blood from patients with neuroblastoma and normal controls was used to assess the phenotype and function of myeloid cells. Polyphenon E reduced the number of tumor-infiltrating myeloid cells, and inhibited the development of spontaneous neuroblastomas in TH-MYCN transgenic mice. In therapeutic models of neuroblastoma in A/J, but not in immunodeficient NOD/SCID mice, Polyphenon E inhibited tumor growth by acting on myeloid-derived suppressor cells (MDSC) and CD8 T cells. In vitro, Polyphenon E impaired the development and motility of MDSCs and promoted differentiation to more neutrophilic forms through the 67 kDa laminin receptor signaling and induction of granulocyte colony-stimulating factor. The proliferation of T cells infiltrating a patient metastasis was reactivated by Polyphenon E. These findings suggest that the neuroblastoma-promoting activity of MDSCs can be manipulated pharmacologically in vivo and that green tea catechins operate, at least in part, through this mechanism.

Highlights of This Issue

Attenuated strains of measles virus are currently assessed in phase I clinical trials as oncolytic viruses able to preferentially infect and kill tumor cells. In addition to the lysis of tumor cells, measles virus vaccine may activate antitumor immune response. To study this phenomenon, Guillerme and colleagues exposed plasmacytoid dendritic cells (pDC), a subset of DC specialized in antiviral immunity, to measles virus vaccine–infected or UV-irradiated tumor cells. Their findings show that only measles virus vaccine–infected cells were able to activate IFN-α production and tumor antigen cross-presentation by pDC. Thus, measles virus vaccine used as an oncolytic virus may recruit pDC in the antitumor immune response.The anticancer activity of green tea catechins has been reported in many laboratory studies and in clinical trials, but the mechanism of action is still unclear. Santilli and colleagues investigated the effect of a clinical grade catechin mixture called Polyphenon E in mouse models of neuroblastoma, a deadly childhood cancer affecting the nervous system. Surprisingly, the differentiation of immunosuppressive myeloid cells and reactivation of the immune system was a key element in the anticancer effect of the catechins. Thus, the nontoxic drug Polyphenon E shows promise as a new therapeutic tool to boost immunologic therapies in children with neuroblastoma.Shin and colleagues examined the underlying molecular mechanism and chemopreventive efficacy of a novel combination of an EGF receptor tyrosine kinase inhibitor with a COX-2 inhibitor, a combination that is being tested in a clinical trial. Preclinical studies confirmed that the combined treatment inhibited growth of head and neck cancer cells with significantly greater potency than either agent alone. Analysis of tissue samples from clinical trial participants consistently showed downregulation of multiple signaling molecules after treatment, which was correlated with clinical response. This investigation of both preclinical studies and the biomarker-driven clinical trial serves as proof-of-principle to justify future chemoprevention trials that target multiple signaling pathways involved in carcinogenesis.Cancer vaccines can be very effective for treating patients, but clinical responses vary widely from one patient to another. Strategies to target treatment to likely responders could significantly improve clinical efficacy, minimize unnecessary side effects, and reduce health care costs. Using a glycan microarray to profile serum antiglycan antibodies, Campbell and colleagues show that prevaccination antibody levels to the blood group A trisaccharide (BG-Atri) are correlated with survival of prostate cancer patients treated with PROSTVAC-VF. Measurement of serum anti-BG-Atri levels prior to vaccination could provide a simple method for preselecting patients who are likely to benefit from PROSTVAC-VF therapy. Additionally, these studies highlight the potential of serum antiglycan antibodies as a convenient reservoir of biomarkers that warrants further investigation.

Selective Adsorption and Separation of (−)-Epigallocatechin Gallate (EGCG) based on Silica Gel Surface Molecularly Imprinted Polymers

To separate and enrich EGCG from a mixture of tea catechins, the molecular imprinted polymers (MIPs) were synthesized on silica gel by surface molecular imprinting technique and characterized with Fourier transform infrared spectroscopy (FT-IR), elemental analysis and scanning electronic microscopy (SEM). MIPs exhibited favorable recognition, better selectivity for EGCG than the other monomers, and the descending order was EGCG, (+)-catechin (C), (−)-epicatechin (EC), (−)-epigallocatechin (EGC), (−)-catechin gallate (CG) and (−)-gallocatechin gallate (GCG). These results demonstrated that MIPs could realize the separation and enrichment of EGCG in real sample.

Flavocoxid (Limbrel ®) manages osteoarthritis through modification of multiple inflammatory pathways: a review

Limbrel (flavocoxid) is marketed as an FDA-regulated medical food for the clinical dietary management of osteoarthritis (OA) to be used under physician supervision. Flavocoxid is composed of a &gt;90% mixture of baicalin and catechin and represents a non-targeted anti-inflammatory which works differently than non-steroidal anti-inflammatory drugs (NSAIDs) that bind to and only inhibit the cyclooxygenase moieties of COX-1 and COX-2. Flavocoxid binds to and weakly modulates the peroxidase activity of the COX enzymes permitting low level expression of prostaglandins (PGs), prostacyclin (PGI2) and thromboxane (TxA2). In addition, flavocoxid weakly inhibits phospholipase A2 (PLA2) and 5-lipoxygenase (5-LOX) as well as increases IϰBα and prevents nuclear factor kappa B (NFϰB) activation/induction of inflammatory genes such as tumor necrosis factor-alpha (TNFα), interleukin-1β (IL-1 β), IL-6, COX-2, inducible nitric oxide synthase (iNOS) and 5-LOX. In clinical studies, flavocoxid shows equivalent efficacy to naproxen with statistically fewer renal (edema) and upper gastrointestinal (GI) side effects, does not affect platelet function and bleeding times, does not change international normalized ratio (INR) in warfarinized patients, is well-tolerated in patients with previous NSAID-induced GI side effects, and decreases or eliminates the use of gastroprotective medications in patients who previously required them to tolerate NSAIDs. With its broad, non-targeted and multiple weak activities which result in fewer side effects compared to NSAIDs, flavocoxid represents a different way managing OA by working on the underlying and multiple causes of cartilage degradation as well as joint inflammation. Keywords: Flavocoxid, Limbrel, osteoarthritis, inflammatory pathways, and medical foods

Polyphenon E 10% ointment: a guide to its use in the treatment of external genital and perianal warts

Polyphenon E 10% ointment (Veregen®), which contains a mixture of green tea catechins, is indicated for the treatment of external genital and perianal warts in immunocompetent adults. Application of polyphenon E 10% ointment for up to 16 weeks was significantly more effective than vehicle in clearing external genital and perianal warts. Local skin reactions at the wart treatment site are very common and are related to the mode of action of the ointment.

Effects of catechin and epicatechin on superoxide dismutase and glutathione peroxidase activity, in vivo

ObjectivesThe objective of this study was to investigate the effects of catechin and epicatechin on the activity of the endogenous antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx) (as well as the total antioxidant capacity (TAC)) of rats after intra-peritoneal (i.p.) administration.MethodsTwenty-four Wistar rats were randomly divided into two groups: the experimental group which was administered daily with a 1:1 mixture of epicatechin and catechin at a concentration of 23 mg/kg body weight for 10 days and the control group which was injected daily with an equal amount of saline. Blood and urine samples were collected before and after the administration period, as well as 10 days after (follow-up).ResultsIntra-peritoneal administration of catechins led to a potent decrease in GPx levels and a significant increase in SOD levels. TAC was significantly increased in plasma and urine. Malonaldehyde levels in urine remained stable. In the animals treated with catechins, SOD activity showed a moderate negative correlation with GPx activity.DiscussionBoosting the activity of the antioxidant enzymes could be a potential adjuvant approach for the treatment of the oxidative stress-related diseases.

Polyphenon E 10% Ointment

Polyphenon E 10% ointment, which contains a mixture of green tea catechins, is indicated for the treatment of external genital and perianal warts (Condylomata acuminata) in immunocompetent patients aged ≥18 years. In two double-blind, multinational studies in adults with external genital and perianal warts, polyphenon E 10% ointment for up to 16 weeks was significantly more effective than vehicle with regard to the complete clearance of all warts (i.e. those at baseline and newly appearing during treatment) [primary endpoint]. In gender subgroup analyses, polyphenon E 10% ointment was more effective than vehicle in both men and women in one of two individual studies, and in pooled data from both studies. Polyphenon E 10% ointment was also significantly more effective than vehicle with regard to several secondary endpoints, including the complete clearance of baseline warts and partial clearance of at least 50% of all warts in both studies. Rates of recurrence of any warts or development of new warts were low (<9%) in both treatment arms during a 12-week follow-up period in both studies. Polyphenon E 10% ointment was generally well tolerated in adults with external genital and perianal warts. According to pooled data from the two clinical studies, the majority of adverse events associated with polyphenon E 10% ointment involved application site and local skin reactions at the treatment site.

Bioactive Phenolic Compounds from the Egyptian Red Sea Seagrass Thalassodendron ciliatum

Five flavonoids (rutin, asebotin, 3-hydroxyasebotin, quercetin-3-O-beta-D-xylopyranoside, and a racemic mixture of catechin) and caffeic acid were isolated and identified for the first time from seagrass, Thalassodendron ciliatum, collected from the Hurghada region in Egypt. The crude extract and the isolated pure compounds were evaluated for their cytotoxic activities against HCT-116, HEPG, MCF-7, and HeLa human cancer cell lines, for their antiviral activity against Herpes Simplex and hepatitis A viruses, and for their antioxidant activity.