Potential Cancer Chemopreventive Activity Research Articles

Bioactivity and Functionality of Anthocyanins: A Review

:Anthocyanins are flavonoid compounds imparting pink, red, blue, and purple colors to fruits, flowers, leaves, and some underground organs. These pigments play an important role in pollination and fruit and seed dispersal and they are related to the protection of plant tissues exposed to biotic and/or abiotic stress. Their consumption has been linked to diverse health benefits such as anti-inflammatory and anti-carcinogenic properties, diminution of cardiovascular disease incidence, obesity control, and diabetes mitigation effects. Also, in vitro studies have revealed certain potential cancer chemopreventive activities of anthocyanins. Reactive oxygen species scavenging as well as metal chelating and direct binding to proteins have been associated with anthocyanin health effects. Recent studies have indicated that these compounds can modulate decisive signaling pathways and gene regulation. Their action contributes to vascular homeostasis and to angiogenesis, inflammation, and platelet aggregation control. Likewise, anthocyanins have been associated with the prevention of a peroxynitrite-mediated disorder in endothelial cells. The potential use of anthocyanins as colorants in food has been extensively analyzed since they are the main hydrosoluble plant pigments. However, their instability and the influence of concentration, pH, temperature, and the presence of other compounds (phenolic acids, metals) on color properties can limit anthocyanin use as food ingredients and additives. Encapsulation has been proposed as an alternative to reduce food-processing damage and to deliver these compounds to their target site in the human body. Likewise, chemical lipophilization of anthocyanins has been assayed to obtain modified compounds with higher lipophilicity, more suitable for lipid-rich matrices.

Inhibition of skin tumor promotion by TPA using a combination of topically applied ursolic acid and curcumin.

Prevention remains an important strategy to reduce the burden of cancer. One approach to prevent cancer is the use of phytochemicals in various combinations as safe and effective cancer preventative agents. The purpose of this study was to examine the effects of the combination of ursolic acid (UA) and curcumin (Curc) for potential combinatorial inhibition of skin tumor promotion using the mouse two-stage skin carcinogenesis model. In short-term experiments, the combination of UA + Curc given topically prior to 12-O-tetradecanoylphorbol-13-acetate (TPA) significantly inhibited activation of epidermal EGFR, p70S6K, NF-κB p50, Src, c-Jun, Rb, and IκBα. Levels of c-Fos, c-Jun, and Cox-2 were also significantly reduced by the combination compared to the TPA treated group. The alterations in these signaling pathways by the combination of UA + Curc were associated with decreased epidermal proliferation as assessed by measuring BrdU incorporation. Significant effects were also seen with the combination on epidermal inflammatory gene expression and dermal inflammation, with the greatest effects on expression of IL-1β, IL-6, IL-22, and CXCL2. Furthermore, results from skin tumor experiments demonstrated that the combination of UA + Curc given topically significantly inhibited mouse skin tumor promotion by TPA to a greater extent than the individual compounds given alone. The greatest effects were seen on tumor free survival, tumor size, and tumor weight, although tumor incidence and multiplicity were also further reduced by the combination. These results demonstrate the potential cancer chemopreventive activity and mechanism(s) for the combination of UA + Curc.

A Review on-Herbs in Anticancer

Cancer is the abnormal growth of cells in our bodies that can lead to death. Cancer is a leading cause of mortality in the world and it's the cause of more than 20% of all deaths. The major problem in the cancer chemotherapy is the toxicity of the established drugs. Some of the natural product extracts are capable of preventing or inhibiting the process of carcinogenesis. Thousands of herbal and traditional compounds are being examine by many searchers worldwide to validate their use as anti-cancerous drugs. Medicinal plants and their use in various traditional systems of medicine are indeed awe-inspiring. General public consider herbal remedies to be safe, as it causes less side-effects and less likely to cause dependency. Various dietary agents that interfere with these stages of cancer, thus blocking malignancy and thus Cancer induction, growth, and progression are multi-step events and numerous studies have beendemonstrated. Fruits and vegetables contains untapped reservoir ofvarious nutritive and non-nutritive phytochemicals with potential cancer chemo-preventiveactivity. Plants have been used for treating diseases since time immemorial. More than 50% of modern drugs in clinical use are of natural products. Study is required to determine the efficacy of these plant products in treating cancers in humans.

Utilization of the Ability to Induce Activation of the Nuclear Factor (Erythroid-derived 2)-like Factor 2 (Nrf2) to Assess Potential Cancer Chemopreventive Activity of Liquorice Samples.

Nuclear factor (erythroid-derived 2)-like factor 2 (Nrf2) is a transcription factor that regulates expression of many detoxification enzymes. Nrf2-antioxidant responsive element (Nrf2-ARE) signalling pathway can be a target for cancer chemoprevention. Glycyrrhiza glabra, common name, 'liquorice', is used as a sweetening and flavouring agent, and traditionally, to treat various ailments, and implicated to chemoprevention. However, its chemopreventive property has not yet been scientifically substantiated. To assess the ability of liquorice root samples to induce Nrf2 activation correlating to their potential chemopreventive property. The ability of nine methanolic extracts of liquorice root samples, collected from various geographical origins, to induce Nrf2 activation was determined by the luciferase reporter assay using the ARE-reporter cell line, AREc32. The antioxidant properties were determined by the 2,2-diphenyl-1-picryhydrazyl (DPPH) and the ferric-reducing antioxidant power (FRAP) assays. All extracts exhibited free-radical-scavenging property (RC50 = 136.39-635.66 µg/mL). The reducing capacity of ferrous ion was 214.46-465.59 μM Fe(II)/g. Nrf2 activation indicated that all extracts induced expression of ARE-driven luciferase activity with a maximum induction of 2.3 fold relative to control. These activities varied for samples from one geographical location to another. The present findings add to the existing knowledge of cancer chemoprevention by plant-derived extracts or purified phytochemicals, particularly the potential use of liquorice for this purpose. Copyright © 2016 John Wiley & Sons, Ltd.

Synthesis of Resveratrol Derivatives and In Vitro Screening for Potential Cancer Chemopreventive Activities.

New resveratrol (trans-3,4',5-trihydroxystilbene) analogs were synthesized and screened for their in vitro cancer chemopreventive potential using various bioassays relevant for the prevention of carcinogenesis in humans: two assays to detect modulators of carcinogen metabolism (Cyp1A inhibition; determination of NAD(P)H/quinone reductase (QR) activity), three assays to identify radical scavenging and antioxidant properties (DPPH, ORAC, superoxide anion radicals in differentiated HL-60 cells), four assays to determine anti-inflammatory and anti-hormonal effects (iNOS, Cox-1 and aromatase inhibition, anti-estrogenic potential). 3,4',5-Tri-O-methyl resveratrol 1a was about sevenfold more active than resveratrol in inhibiting Cyp1A activity, it was a potent inducer of QR activity, and it showed pure anti-estrogenic activity (whereas resveratrol is a known mixed estrogen (ant)agonist with both estrogenic and anti-estrogenic properties). Dual estrogen ant-/agonist activity was restored in the mono-O-benzyl-substituted derivatives 4b (4'-O-benzyl resveratrol) and 5b (3-O-benzyl resveratrol). With respect to aromatase inhibition (Cyp19), which provided the highest number of actives, the benzyl-substituted series was more potent than the methyl-substituted derivatives of resveratrol, and 3-O-benzyl resveratrol 5b was about eightfold more active than resveratrol. Overall, 3,4',5-tri-O-pivaloyl resveratrol oxide 7c was identified as a potent inducer of phase 2 enzymes concomitant with inhibition of LPS-mediated iNOS induction.

Potential cancer chemopreventive activity of some goji berry pyrrole alkaloids isolated from a mislabeled commercial sample

Goji berry [fruit of Lycium barbarum L. (Solanaceae)] has a long history of usage in Asian countries as a culinary ingredient, traditional medicine and functional food. Goji has more recently become increasingly popular in Europe and North America as a “super fruit” and botanical dietary supplement. One commercial dietary supplement that was screened in an ongoing search for natural inhibitors of carcinogenesis showed hydroxyl radical-scavenging (HRS) and quinone reductase-inducing (QRI) activities. This sample was shown by chemotaxonomy and microscopy to be mislabeled, and was identified as Goji. Isolation directed by the above bioassays yielded a new pyrrole alkaloid (1) along with seven known compounds (2 – 8). Compound 1 demonstrated HRS activity with an ED50 value of 16.7 µM, and compound 2 was active in both HRS (ED50 11.9 µM) and QRI [CD (concentration required to double quinone reductase activity) 2.4 µM)] assays. Further investigation confirmed the presence of compounds 1 – 2 and 4 – 8 in a Goji extract that was previously shown to prevent N-nitrosomethylbenzylamine-induced esophageal cancer in rats. Taken together with the dietary source of these molecules having a long history of human consumption, the results of the study indicated that this class of compounds, especially compound 2, could be potential in vivo cancer chemopreventive agents.

Pyrrole alkaloids with potential cancer chemopreventive activity isolated from a goji berry-contaminated commercial sample of African mango.

Bioassay-guided fractionation of a commercial sample of African mango (Irvingia gabonensis) that was later shown to be contaminated with goji berry (Lycium sp.) led to the isolation of a new pyrrole alkaloid, methyl 2-[2-formyl-5-(hydroxymethyl)-1H-pyrrol-1-yl]propanoate, 1, along with seven known compounds, 2–8. The structures of the isolated compounds were established by analysis of their spectroscopic data. The new compound 1g showed hydroxyl radical-scavenging activity with an ED50 value of 16.7 μM, whereas 4-[formyl-5-(methoxymethyl)-1H-pyrrol-1-yl]butanoic acid (2) was active in both the hydroxyl radical-scavenging (ED50 11.9 μM) and quinone reductase-induction [CD (concentration required to double QR activity) 2.4 μM)] assays used. The isolated compounds were shown to be absent in a taxonomically authenticated African mango sample but present in three separate authentic samples of goji berry (Lycium barbarum) using LC-MS and 1H NMR fingerprinting analysis, including one sample that previously showed inhibitory activity in vivo in a rat esophageal cancer model induced with N-nitrosomethylbenzylamine. Additionally, microscopic features characteristic of goji berry were observed in the commercial African mango sample.

Suppression of Src/ERK and GSK-3/β-catenin signaling by pinosylvin inhibits the growth of human colorectal cancer cells

Pinosylvin, a naturally occurring trans-stilbenoid mainly found in Pinus species, has exhibited a potential cancer chemopreventive activity. However, the growth inhibitory activity against cancer cells and the underlying molecular mechanisms remain to be elucidated. Therefore, the anti-proliferative activity of pinosylvin was investigated in human colorectal HCT 116 cancer cells. Pinosylvin inhibited the proliferation of HCT 116 cells by arresting transition of cell cycle from G1 to S phase along with the downregulation of cyclin D1, cyclin E, cyclin A, cyclin dependent kinase 2 (CDK2), CDK4, c-Myc, and retinoblastoma protein (pRb), and the upregulation of p21(WAF1/CIP1) and p53. Pinosylvin was also found to attenuate the activation of proteins involved in focal adhesion kinase (FAK)/c-Src/extracellular signal-regulated kinase (ERK) signaling, and phosphoinositide 3-kinase (PI3K)/Akt/ glycogen synthase kinase 3β (GSK-3β) signaling pathway. Subsequently, pinosylvin suppressed the nuclear translocation of β-catenin, one of downstream molecules of PI3K/Akt/GSK-3β signaling, and these events led to the sequential downregulation of β-catenin-mediated transcription of target genes including BMP4, ID2, survivin, cyclin D1, MMP7, and c-Myc. These findings demonstrate that the anti-proliferative activity of pinosylvin might be associated with the cell cycle arrest and downregulation of cell proliferation regulating signaling pathways in human colorectal cancer cells.

Antimetastatic activity of pinosylvin, a natural stilbenoid, is associated with the suppression of matrix metalloproteinases

Metastasis is a major cause of death in cancer patients. Our previous studies showed that pinosylvin, a naturally occurring trans-stilbenoid mainly found in Pinus species, exhibited a potential cancer chemopreventive activity and also inhibited the growth of various human cancer cell lines via the regulation of cell cycle progression. In this study, we further evaluated the potential antimetastatic activity of pinosylvin in in vitro and in vivo models. Pinosylvin suppressed the expression of matrix metalloproteinase (MMP)-2, MMP-9 and membrane type 1-MMP in cultured human fibrosarcoma HT1080 cells. We also found that pinosylvin inhibited the migration of HT1080 cells in colony dispersion and wound healing assay systems. In in vivo spontaneous pulmonary metastasis model employing intravenously injected CT26 mouse colon cancer cells in Balb/c mice, pinosylvin (10 mg/kg body weight, intraperitoneal administration) significantly inhibited the formation of tumor nodules and tumor weight in lung tissues. The analysis of tumor in lung tissues indicated that the antimetastatic effect of pinosylvin coincided with the down-regulation of MMP-9 and cyclooxygenase-2 expression, and phosphorylation of ERK1/2 and Akt. These data suggest that pinosylvin might be an effective inhibitor of tumor cell metastasis via modulation of MMPs.

Neocarzinostatin as a probe for DNA protection activity—molecular interaction with caffeine

Neocarzinostatin (NCS), a potent mutagen and carcinogen, consists of an enediyne prodrug and a protein carrier. It has a unique double role in that it intercalates into DNA and imposes radical-mediated damage after thiol activation. Here we employed NCS as a probe to examine the DNA-protection capability of caffeine, one of common dietary phytochemicals with potential cancer-chemopreventive activity. NCS at the nanomolar concentration range could induce significant single- and double-strand lesions in DNA, but up to 75 ± 5% of such lesions were found to be efficiently inhibited by caffeine. The percentage of inhibition was caffeine-concentration dependent, but was not sensitive to the DNA-lesion types. The well-characterized activation reactions of NCS allowed us to explore the effect of caffeine on the enediyne-generated radicals. Postactivation analyses by chromatographic and mass spectroscopic methods identified a caffeine-quenched enediyne-radical adduct, but the yield was too small to fully account for the large inhibition effect on DNA lesions. The affinity between NCS chromophore and DNA was characterized by a fluorescence-based kinetic method. The drug-DNA intercalation was hampered by caffeine, and the caffeine-induced increases in DNA-drug dissociation constant was caffeine-concentration dependent, suggesting importance of binding affinity in the protection mechanism. Caffeine has been shown to be both an effective free radical scavenger and an intercalation inhibitor. Our results demonstrated that caffeine ingeniously protected DNA against the enediyne-induced damages mainly by inhibiting DNA intercalation beforehand. The direct scavenging of the DNA-bound NCS free radicals by caffeine played only a minor role.

Nuclear Factor E2–Related Factor 2–Mediated Induction of NAD(P)H:Quinone Oxidoreductase 1 by 3,5-Dimethoxy-trans-stilbene

NAD(P)H:quinone oxidoreductase 1 (NQO1), a phase II enzyme, plays an important role in the detoxification or chemoprotection of carcinogens, and induction of this enzyme is a target for the prevention of carcinogenesis. Natural stilbenoids have potential cancer chemopreventive activities, potentially through affecting NQO1 activity. Along this line, several stilbenoids were evaluated to procure more potent compounds for inducing NQO1 activity in cultured murine Hepa 1c1c7 cells. As a result, we found that 3,5-dimethoxy-trans-stilbene (DMS) possesses potent NQO1 induction activity through up-regulation of both protein and mRNA expression of NQO1 as determined by Western blot and reverse transcription-polymerase chain reaction analysis, respectively. DMS also increased protein expression of heme oxygenase-1 (HO-1), another phase II enzyme. This induction of NQO1 and HO-1 by DMS was closely related to the regulation of nuclear factor E2-related factor 2 (Nrf2). The translocation and activation of Nrf2 by DMS was also involved in the modulation of the upstream signal transduction molecule, protein kinase C δ. These findings suggest that DMS might have a cancer chemopreventive activity by inducing detoxifying enzymes such as NQO1 and HO-1.

Phthalate esters reveal skin-sensitizing activity of phenethyl isothiocyanate in mice

Phenethyl isothiocyanate (PEITC) is a constituent of edible cruciferous vegetables and has received attention due to its potential cancer chemopreventive activity. Although its protein-binding activity is known, PEITC has not been studied as a contact sensitizer. We previously demonstrated that phthalate esters, including dibutyl phthalate (DBP) and di-n-propyl phthalate (DPP), enhance skin sensitization in a fluorescein isothiocyanate (FITC)-induced contact hypersensitivity mouse model. In this study, we examined whether DBP and DPP enhance skin sensitization to haptens other than FITC. During this study, we tested PEITC as a contact sensitizer. BALB/c mice were epicutaneously sensitized with a suboptimal dose of a hapten with or without a phthalate ester. Sensitization was evaluated as the ear swelling response after a challenge with the respective hapten. DBP and DPP did not enhance the sensitization to two T-helper 1-type (2,4-dinitrofluorobenzene and oxazolone) or three T-helper 2-type (trimellitic anhydride, methylenediphenyl 4,4′-diisocyanate, and tolulene 2,4-diisocyanate) haptens. In contrast, DBP and DPP enhanced the sensitization to two FITC analogues (eosin 5-isothiocyanate and rhodamine B isothiocyanate) as well as to PEITC. Adjuvant effects of DBP and DPP were observed in contact hypersensitivity to haptens other than FITC, including a food ingredient PEITC.

A transcriptomic computational analysis of mastic oil-treated Lewis lung carcinomas reveals molecular mechanisms targeting tumor cell growth and survival

BackgroundMastic oil from Pistacia lentiscus variation chia, a blend of bioactive terpenes with recognized medicinal properties, has been recently shown to exert anti-tumor growth activity through inhibition of cancer cell proliferation, survival, angiogenesis and inflammatory response. However, no studies have addressed its mechanisms of action at genome-wide gene expression level.MethodsTo investigate molecular mechanisms triggered by mastic oil, Lewis Lung Carcinoma cells were treated with mastic oil or DMSO and RNA was collected at five distinct time points (3-48 h). Microarray expression profiling was performed using Illumina mouse-6 v1 beadchips, followed by computational analysis. For a number of selected genes, RT-PCR validation was performed in LLC cells as well as in three human cancer cell lines of different origin (A549, HCT116, K562). PTEN specific inhibition by a bisperovanadium compound was applied to validate its contribution to mastic oil-mediated anti-tumor growth effects.ResultsIn this work we demonstrated that exposure of Lewis lung carcinomas to mastic oil caused a time-dependent alteration in the expression of 925 genes. GO analysis associated expression profiles with several biological processes and functions. Among them, modifications on cell cycle/proliferation, survival and NF-κB cascade in conjunction with concomitant regulation of genes encoding for PTEN, E2F7, HMOX1 (up-regulation) and NOD1 (down-regulation) indicated some important mechanistic links underlying the anti-proliferative, pro-apoptotic and anti-inflammatory effects of mastic oil. The expression profiles of Hmox1, Pten and E2f7 genes were similarly altered by mastic oil in the majority of test cancer cell lines. Inhibition of PTEN partially reversed mastic oil effects on tumor cell growth, indicating a multi-target mechanism of action. Finally, k-means clustering, organized the significant gene list in eight clusters demonstrating a similar expression profile. Promoter analysis in a representative cluster revealed shared putative cis-elements suggesting a common regulatory transcription mechanism.ConclusionsPresent results provide novel evidence on the molecular basis of tumor growth inhibition mediated by mastic oil and set a rational basis for application of genomics and bioinformatic methodologies in the screening of natural compounds with potential cancer chemopreventive activities.

Protective Activity of Theobroma cacao L. Phenolic Extract on AML12 and MLP29 Liver Cells by Preventing Apoptosis and Inducing Autophagy

Theobroma cacao L. is known to have potential cardiovascular and cancer chemopreventive activities because of its high content of phenolic phytochemicals and their antioxidant capacities. In this work, we show for the first time that cocoa inhibits drug-triggered liver cytotoxicity by inducing autophagy. Phenolic-rich extracts of both unroasted and roasted cocoa prevented Celecoxib-induced cell viability inhibition in MLP29 liver cells because of the accumulation of G1 cells and cell death. Death prevented by cocoa had hallmarks of apoptosis such as the sub-G1 peak at flow cytometry and activation of Bax expression, together with down-regulation of Bcl-2, released cytochrome c in the cytosol with activation of Caspase 3, indicating that components of the apoptotic pathway such as Bax or upstream are major targets of cocoa phytochemicals. The protective effect of cocoa against liver cytotoxicity by Celecoxib was probably accounted for by inducing the autophagic process, as shown by enhanced Beclin 1 expression and accumulation of monodansylcadaverine in autolysosomes. This fact suggests that apoptosis was prevented by inducing autophagy. Finally, considering all these findings, we suggest that cocoa can be added to the list of natural chemopreventive agents whose potential in hepatopathy prevention and therapy should be evaluated.

Unraveling the Relationship between Grapes and Health1–4

As described in this Supplement and elsewhere, consumption of grapes or grape products has been associated with various health benefits. Resveratrol is a unique component of grapes. Following our report on potential cancer chemopreventive activity, thousands of studies have been performed to characterize the mode of action of this substance. Nonetheless, scores of additional chemicals are known to be constituents of grapes, several of which are capable of mediating biological responses. Accordingly, when considering grapes and health, a holistic view appears to be more meaningful, taking into account all chemical components, metabolism, biological potential, biodistribution, absorption, processing, etc. To fathom such a massive amount of information, we propose the creation of focused ontologies. Grapes seem reasonable as a test bed for exploring this approach, especially because a fair amount of results are available with whole-grape powder. In essence, by utilizing a next generation intelligent system, attempts can be made to leverage the existing complexity. This approach involves bringing together all available information, together with expert judgment, and processing this information through a computational “engine” or engines to provide suggested solutions (or implicit functional relationships). Accomplishment of this task, employing grapes as a prototype, could lead to broader application by incorporating the myriad of features associated with other fruits and vegetables. The ability to correlate heretofore-uncharacterized “signatures” with biologic outcome could fundamentally transform copious amounts of disparate information into a coherent explanation of human disease prevention.

Anticancer and Cancer Chemopreventive Potential of Grape Seed Extract and Other Grape-Based Products1–3

With emerging trends in the incidence of cancer of various organ sites, additional approaches are needed to control human malignancies. Intervention or prevention of cancer by dietary constituents, a strategy defined as chemoprevention, holds great promise in our conquest to control cancer, because it can be implemented on a broader population base with less economic burden. Consistent with this, several epidemiological studies have shown that populations that consume diets rich in fruits and vegetables have an overall lower cancer incidence. Based on these encouraging observations, research efforts from across the globe have focused on identifying, characterizing, and providing scientific basis to the efficacy of various phytonutrients in an effort to develop effective strategy to control various human malignancies. Cancer induction, growth, and progression are multi-step events and numerous studies have demonstrated that various dietary agents interfere with these stages of cancer, thus blocking malignancy. Fruits and vegetables represent untapped reservoir of various nutritive and nonnutritive phytochemicals with potential cancer chemopreventive activity. Grapes and grape-based products are one such class of dietary products that have shown cancer chemopreventive potential and are also known to improve overall human health. This review focuses on recent advancements in cancer chemopreventive and anticancer efficacy of grape seed extract and other grape-based products. Overall, completed studies from various scientific groups conclude that both grapes and grape-based products are excellent sources of various anticancer agents and their regular consumption should thus be beneficial to the general population.

8-Prenylnaringenin inhibits epidermal growth factor-induced MCF-7 breast cancer cell proliferation by targeting phosphatidylinositol-3-OH kinase activity

8-Prenylnaringenin (8PN), one of the strongest plant-derived oestrogen receptors (ERs) ligand, has been suggested to have potential cancer chemo-preventive activities and anti-angiogenic properties. Because published data suggest that ERs serve as nodal point that allows interactions between hormones and growth factors mediated pathways, we decided to investigate the effects exerted by 8PN on Epidermal growth factor (EGF)-elicited pathways in breast cancer cells. Here we show that in ER positive MCF-7 cells, 8PN interferes with EGF induced cell proliferation by strongly inhibiting activation of PI(3)K/Akt pathway, without affecting EGFR expression or tyrosine phosphorylation, and exerting a synergistic activation of Erk1/2 phosphorylation. Moreover, we demonstrate that 8PN is a direct inhibitor of PI(3)K activity as it is shown by in vitro experiments with the purified enzyme and by its inability to impair serine phosphorylation of a constitutive active form of Akt. These findings suggest that inhibition of PI(3)K is a novel mechanism which contributes to 8PN activity to inhibit cancer cell survival and EGF induced proliferation.

Structural Characterization, Biological Effects, and Synthetic Studies on Xanthones from Mangosteen (Garcinia mangostana), a Popular Botanical Dietary Supplement.

Mangosteen (Garcinia mangostana L., Clusiaceae) is a popular botanical dietary supplement in the United States, where it is used principally as an antioxidant. It is referred to as the "queen of fruits" in Thailand, a country of origin. The major secondary metabolites of mangosteen, the xanthones, exhibit a variety of biological activities including antibacterial, antifungal, antiinflammatory, antioxidant, antiplasmodial, cytotoxic, and potential cancer chemopreventive activities. Moreover, some of the xanthones from mangosteen have been found to influence specific enzyme activities, such as aromatase, HIV-1 protease, inhibitor κB kinase, quinone reductase, sphingomyelinase, topoisomerase and several protein kinases, and they also modulate histamine H(1) and 5-hydroxytryptamine(2A) receptor binding. Several synthetic procedures for active xanthones and their analogs have been conducted to obtain a better insight into structure-activity relationships for this compound class. This short review deals with progress made in the structural characterization of the chemical constituents of mangosteen, as well as the biological activity of pure constituents of this species and synthetic methods for the mangosteen xanthones.

Transport, deglycosylation, and metabolism of trans-piceid by small intestinal epithelial cells

Numerous epidemiological and animal studies have shown that consumption of red wine is related to reduced incidence of cardiovascular diseases and cancer. Trans-resveratrol (3, 5, 4'-trihydroxystilbene), a phenolic compound present in wine, has been reported to have a potential cancer chemopreventive activity. Moreover, it may exert a protective effect against atherogenesis through its antioxidant properties. Trans-piceid (3-ss glucoside of trans-resveratrol) is present to a greater extent than its aglycone in red wine, but hydrolysis of this glycosylated derivative can occur in small intestine and liver, which would enhance the amount of the biological active trans-resveratrol. The present study aimed to investigate the rate of transepithelial transport of trans-piceid using human intestinal Caco-2 cell monolayers and metabolism of this compound during its absorption across the small intestine. The transport of trans-piceid was evaluated in the human epithelial cell line Caco-2, which possesses enterocyte-like properties in vitro. For transepithelial experiments, confluent monolayers of Caco-2 cells were grown on Transwell inserts. For metabolic studies, we used both Caco-2 cells seeded on 6-well plates and rat small intestine cell-free extracts. The time course of apical (AP) to basolateral (BL) transport of trans-piceid showed that the favorable apparent permeability coefficient (Papp) declined rapidly during the 6 h of the experiment. This observation could be correlated with the appearance of metabolites. After incubation of Caco-2 cells with trans-piceid, trans-resveratrol was detected on both AP and BL sides. By using protein extracts obtained from rat, we conclude that the Lactase Phlorizin Hydrolase (LPH) and Cytosolic-ss-Glucosidase (CBG) are involved in the hydrolysis of trans-piceid. Furthermore, we show that after deglycosylation, the resulting aglycone is metabolized in trans-resveratrol-3-O-ss-glucuronide and to a lesser extent in trans-resveratrol-4'-O-ss-glucuronide, and that UGT1A1 is mainly involved in this metabolism. This study demonstrates that the transepithelial transport of trans-piceid occurs at a high rate and that the compound is deglycosylated in trans-resveratrol. There are two possible pathways by which trans-piceid is hydrolyzed in the intestine. The first is a cleavage by the CBG, after passing the brush-border membrane by SGLT1. The second is deglycosylation on the luminal side of the epithelium by the membrane-bound enzyme LPH, followed by passive diffusion of the released aglycone, which is further metabolized inside the cells into two glucuronoconjugates.

Mechanisms of the antiangiogenic activity by the hop flavonoid xanthohumol: NF‐κB and Akt as targets

Xanthohumol (XN), the principal flavonoid of the hop plant (Humulus lupulus L.) and a constituent of beer, has been suggested to have potential cancer chemopreventive activities. We have observed that most cancer chemopreventive agents show antiangiogenic properties in vitro and in vivo, a concept we termed "angioprevention." Here we show for the first time that XN can inhibit growth of a vascular tumor in vivo. Histopathology and in vivo angiogenesis assays indicated that tumor angiogenesis inhibition was involved. Further, we show the mechanisms for its inhibition of angiogenesis in vivo and related endothelial cell activities in vitro. XN repressed both the NF-kappaB and Akt pathways in endothelial cells, indicating that components of these pathways are major targets in the molecular mechanism of XN. Moreover, using in vitro analyses, we show that XN interferes with several points in the angiogenic process, including inhibition of endothelial cell invasion and migration, growth, and formation of a network of tubular-like structures. Our results suggest that XN can be added to the expanding list of antiangiogenic chemopreventive drugs whose potential in cancer prevention and therapy should be evaluated.