Epstein-Barr Virus Early Antigen Activation Research Articles

Chemical constituents of Garcinia fusca: structure elucidation of eight new xanthones and their cancer chemopreventive activity.

We describe the isolation and spectrometric structure elucidation of eight new xanthones, fuscaxanthone A (1), B (2), C (3), D (4), E (5), F (6), G (7), and H (8), together with eight known xanthones from the stem bark of Garcinia fusca collected in Thailand. All the new xanthones were shown to have a terpenoid (prenyl and/or geranyl) side chain(s) in their molecules. We also present the results of a primary screening of the inhibitory effects of eight xanthones (9-16) isolated as major components of this plant on 12-O-tetradecanoylphorbol-13-acetate induced Epstein-Barr virus early antigen activation in Raji cells.

Three new quassinoids, ailantinol E, F, and G, from Ailanthus altissima.

Three new quassinoids, ailantinol E (1), ailantinol F (2), and ailantinol G (3), and related compounds were isolated from Ailanthus altissima grown in Taiwan. Their structures were elucidated from spectral evidence. Each new quassinoid was evaluated for its antitumor promoting effects against Epstein-Barr virus early antigen activation introduced by 12-O-tetradecanoylphorbol-13-acetate in Raji cells. The new quassinoids were found to show potent activity without showing any cytotoxicity. The screening for inhibitors against nitric oxide donor action was also conducted using the new quassinoids and some standard samples.

Ichthyotoxic and anticarcinogenic effects of triterpenoids from Sandoricum koetjape bark.

After bioassay-guided fractionation of the extract from Sandoricum koetjape bark, which exhibited significant toxicity to killifish (Oryzias latipes), two ichthyotoxic triterpenoids were isolated and characterized as koetjapic acid and 3-oxo-olean-12-en-29-oic acid. These constituents, along with non-toxic katonic acid, had a remarkable inhibitory effect on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol 13-acetate (TPA), which is a preliminary in vitro screening method for possible anti-tumor-promoting agents. Of the triterpenoids active in vitro, koetjapic acid appears to be a promising cancer chemopreventive agent, since it significantly delayed tumor promotion in two-stage mouse skin carcinogenesis induced by 7,12-dimethylbenz(a)anthracene and promoted by TPA.

Potential Antitumor-Promoting Diterpenes from the Cones of Pinus luchuensis

A new nor-labdane-type diterpene, 15-nor-labda-8(17),12E-dien-13,19-dienoic acid (1), along with five known diterpenes, 15-nor-14-oxolabda-8(17),12E-dien-19-oic acid (2), trans-communic acid (3), sandaracopimaric acid (4), dehydroabietic acid (5), and abieta-8,11,13-triene-15,18-diol (6), was isolated from the cones of Pinus luchuensis. The structure of 1 was established by chemical and spectroscopic methods. Among these isolates, compounds 2, 4, and 6 showed potent inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate.

Cancer chemopreventive effect of quassinoid derivatives. Introduction of side chain to shinjulactone C for enhancement of inhibitory effect on Epstein–Barr virus activation

A series of shinjulactone C ( 1) derivatives ( 2– 8) were synthesized and evaluated for their anti-tumor promoting effects against Epstein–Barr virus early antigen activation introduced by 12- O-tetradecanoylphorbol-13-acetate in Raji cells. The succinate and 3′,3′-dimethylsuccinate derivatives of 1 exhibited higher inhibitory effects than 1. From the point of view of structure–activity relationships, the succinate derivatives ( 2, 4) demonstrated better potency than the glutarate derivatives ( 3, 5– 8). As substituted moieties of 3′-position became bulky, the inhibitory effects of the glutarate derivatives ( 7, 8) significantly decreased.

Interiotherins C and D, two new lignans from Kadsura interior and antitumor-promoting effects of related neolignans on Epstein-Barr virus activation.

Two new lignans, interiotherins C (1) and D (2), together with the known compounds interiorin (3), heteroclitin F (4), neokadsuranin (5), heteroclitin D (6), kadsurin (7), gomisin A (8), schisandrin C (9), interiotherin A (10), angeloylgomisin R (11), gomisin G (12), interiotherin B (13), and gomisin C (14), were isolated from the stems of Kadsura interior. The structures and stereochemistries of the new compounds were determined from mass, CD, and NMR spectral data. Fourteen neolignans were screened as potential antitumor promoters by examining their ability to inhibit Epstein-Barr virus early antigen (EBV-EA) activation (induced by 12-O-tetradecanoylphorbol-13-acetate) in Raji cells. Neokadsuranin (5) and schisandrin C (9) were the most potent compounds. These data suggest that some neolignans might be valuable antitumor promoters or chemopreventors.

Chemopreventive effect of resveratrol, sesamol, sesame oil and sunflower oil in the epstein–barr virus early antigen activation assay and the mouse skin two-stage carcinogenesis

Resveratrol, sesamol, sesame oil and sunflower oil are known natural dietary components with intrinsic cancer chemopreventive potentials. As a part of our study of dietary constituents as potential cancer chemopreventive agents, we have assessed the anti-cancer potentials of these products in the promotion stage of cancer development employing the in vitro Epstein–Barr virus early antigen activation assay induced by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA). Further, we studied the activities of these compounds in the brine shrimp cytotoxicity assay as well as on the stable 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging bioassay with a view to comparing some of the mechanisms of their anti-cancer activity. Finally, we compared the observed chemoprotective capabilities of the four products in the in vivo 7,12 dimethylbenz(a)anthracene initiated and TPA-promoted mouse skin two-stage carcinogenesis protocols. All the products tested showed a profound inhibitory effect on the Epstein–Barr virus early antigen induction using Raji cells. Comparatively, sesame oil was the most potent followed by sesamol and then resveratrol. Only sesamol and resveratrol showed a remarkable cytotoxic activity in the brine shrimp lethality assays as well as profound free radical scavenging activity in the DPPH bioassay. In both test systems, sesamol exhibited a more remarkable activity than resveratrol while sesame oil and sunflower oil did not exhibit any appreciable activity even at the highest concentrations tested (4000 μ g ml−1 ). In our in vivo assay at a 50-fold molar ratio to TPA, sesamol offered 50% reduction in mouse skin papillomas at 20 weeks after promotion with TPA. Under an identical molar ratio to TPA, resveratrol offered a 60% reduction in the papillomas in mouse at 20 weeks. Thus sesamol seems to be an almost equally potent chemopreventive agent. Sesame oil and sunflower oil offered 20 and 40% protection, respectively, in the mouse skin tumor model. The anti-oxidant capabilities of these compounds could not solely explain the observed anti-cancer characteristics. Resveratrol is present in grapes. Sesamol, a constituent of sesame oil and sunflower oil are regularly consumed dietary natural products. The observed chemopreventive effect of these products particularly warrants more attention since they already exist in the population with no known adverse effects.

Inhibitory effect of herbal remedies on 12-o-tetradecanoylphorbol-13-acetate-promoted Epstein–Barr virus early antigen activation

For the past several years we have been evaluating natural products as potential cancer chemopreventive agents in a short term in vitroassay involving Epstein–Barr virus early antigen (EBV-EA) activation in Raji cells promoted by phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA). Because of the current interest in the use of herbal remedies, we considered examining them for their cancer chemopreventive activities, using their extracts with a view to uncovering such benefits (if any) these remedies might possess. Thirty-six extracts of 32 herbs belonging to 27 families in use as herbal remedies including those of gingko, black cohosh, echinacea, kava-kava, saw palmetto, turmeric, angelica, wild yam, cat’s claw, passion flower, muira puama, feverfew, blueberry, chasteberry, licorice, nettle, golden seal, pygeum, ginger, valerian and hops were prepared and evaluated. Turmeric at a concentration of 10 μg ml −1exhibited the most potent anti-EBV-EA activity, which is ten times more than passionflower, that is next in the order of activity. At the concentration level of 100 μg ml −1, several of the herbal remedies tested inhibited the EBV-EA in Raji cells exposed to the tumor promoter TPA (32 pM) by more than 90%. We also report for the first time the activities of 16 new medicinal plants as potential cancer chemopreventive agents. Since inhibitors of EBV-EA promoted by TPA in vitrohave been shown to be effective anti-tumor promoting agents in laboratory animal models, our results indicate new and potential applications of these herbal remedies as cancer chemopreventive agents since they are already in clinical use in the human population.

Chemical constituents of Calophyllum brasiliensis: structure elucidation of seven new xanthones and their cancer chemopreventive activity.

The first study of chemical constituents of the stem bark of Calophyllum brasilienses collected in Brazil has led to the isolation and identification of seven new xanthones named brasixanthones A (1), B (4), C (5), D (6), E (2), F (3), and G (10), together with 10 known xanthones. Among the xanthones isolated in this study, 4, 5, 6, and 11 were found to exhibit significant inhibitory activity against 12-O-tetradecanoylphorbol-13-acetate induced Epstein-Barr virus early antigen activation in Raji cells.

Anti-inflammatory and anti-tumor-promoting effects of cucurbitane glycosides from the roots of Bryonia dioica.

Seven new triterpene glycosides, bryoniosides A-G (1-7), have been isolated along with two known triterpene glycosides, cabenoside D (8) and bryoamaride (9), from a methanol extract of the roots of Bryoniadioica. The structures of 1-7 were determined on the basis of spectroscopic and chemical methods. Six compounds, 2, 3, 5, and 7-9, and 11 compounds, 1-9, bryodulcosigenin (10), and bryosigenin (11), respectively, were evaluated for their inhibitory effects on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation (1 microg/ear) in mice and on Epstein-Barr virus early antigen (EBV-EA) activation induced by TPA. All compounds tested showed marked anti-inflammatory effects, with 50% inhibitory doses (ID(50)) of 0.2-0.6 mg per ear. In addition, all of the compounds tested except for compound 5 showed potent inhibitory effects on EBV-EA induction (100% inhibition at 1 x 10(3) mol ratio/TPA).

Eupha-7,9(11),24-trien-3beta-ol ("antiquol C") and other triterpenes from Euphorbia antiquorum latex and their inhibitory effects on Epstein-Barr virus activation.

The structures of three triterpene alcohols isolated from the latex of Euphorbia antiquorum were established to be eupha-7,9(11),24-trien-3beta-ol (2; antiquol C), 19(10-->9)abeo-8alpha,9beta,10alpha-eupha-5,24-dien-3beta-ol (3; antiquol B), and 24-methyltirucalla-8,24(24(1))-dien-3beta-ol (4; euphorbol) on the basis of spectroscopic methods. Compounds 3 and 4 have previously been assigned the erroneous structures of 10alpha-cucurbita-5,24-dien-3alpha-ol and 24-methyleupha-8,24(24(1))-dien-3beta-ol, respectively. Compounds 2-4 and four other known compounds isolated from the latex, euphol (1), lemmaphylla-7,21-dien-3beta-ol (5), isohelianol (6), and camelliol C (7), showed potent inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA).

Cancer chemopreventive activity of Achyranthes aspera leaves on Epstein–Barr virus activation and two-stage mouse skin carcinogenesis

Achyranthes aspera leaves have been assessed for chemopreventive activity. The MeOH extract, alkaloid, non-alkaloid and saponin fractions exhibited significant inhibitory effects (concentration 100 μg) on the Epstein–Barr virus early antigen activation induced by the tumor promotor 12- O-tetradecanoylphorbol-13-acetate in Raji cells. In this in vitro assay the non-alkaloid fraction containing mainly non-polar compounds showed the most significant inhibitory activity (96.9%; 60% viability). In the in vivo two-stage mouse skin carcinogenesis test the total methanolic extract possessed a pronounced anticarcinogenic effect (76%). The present study suggests that A. aspera leaf extract and the non-alkaloid fraction are valuable antitumor promotors in carcinogenesis.

Constituents of Compositae plants: III. Anti-tumor promoting effects and cytotoxic activity against human cancer cell lines of triterpene diols and triols from edible chrysanthemum flowers

Fifteen pentacyclic triterpene diols and triols, consisting of: six taraxastanes, faradiol ( 1), heliantriol B 0 ( 2), heliantriol C ( 3), 22α-methoxyfaradiol ( 4), arnidiol ( 5), and faradiol α-epoxide ( 6); five oleananes, maniladiol ( 7), erythrodiol ( 8), longispinogenin ( 9), coflodiol ( 10), and heliantriol A 1 ( 11); two ursanes, brein ( 12) and uvaol ( 13); and two lupanes, calenduladiol ( 14) and heliantriol B 2 ( 15), isolated from the non-saponifiable lipid fraction of the edible flower extract of chrysanthemum ( Chrysanthemum morifolium) were evaluated for their inhibitory effects on Epstein–Barr virus early antigen (EBV-EA) activation induced by the tumor promoter, 12- O-tetradecanoylphorbol-13-acetate, in Raji cells as a primary screening test for anti-tumor-promoters. All of the compounds tested showed inhibitory effects against EBV-EA activation with potencies either comparable with or stronger than that of glycyrrhetic acid, a known natural anti-tumor-promoter. Evaluation of the cytotoxic activity of six compounds, 1– 3 and 5– 7, against human cancer cell lines revealed that compound 5 possesses a wide range of cytotoxicity, with GI 50 values (concentration that yields 50% growth) of mostly less than 6 μM.

Cancer chemopreventive activity of naphthoquinones and their analogs from Avicennia plants

As a part of screening studies for cancer chemopreventive agents (anti-tumor promoters), six natural and four synthetic naphthoquinones and five of their analogs were tested for their inhibitory activities against Epstein–Barr virus early antigen activation induced by 12- O-tetradecanoylphorbol-13-acetate in Raji cells. Some of the 1,4-naphthoquinones and their analogs were found to show remarkably potent activities, without showing any cytotoxicity. 1,4-Furanonaphthoquinone (5) and its analog (9) isolated from Avicennia plants (Avicenniaceae), having an alcoholic OH group on the dihydrofuran-ring, displayed the most potent activity. Furthermore, avicenol-A (9) exhibited a marked inhibitory effect on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test. The result of the present investigation indicated that some of these 1,4-naphthoquinones and their analogs might be valuable as potent cancer chemopreventive agents.

Inhibitory effect of flavonoid derivatives on Epstein–Barr virus activation and two-stage carcinogenesis of skin tumors

To search for possible anti-tumor promoters, ten flavonoid derivatives ( 1– 10) synthesized from morin and quercetin were examined for their inhibitory effects on the Epstein–Barr virus early antigen (EBV-EA) activation by a short-term in vitro assay. Of these compounds, pentaallyl ethers ( 9, 10) showed significant inhibitory effects on EBV-EA activation induced by the tumor promoter, 12- O-tetradecanoylphorbol 13-acetate. Further, quercetin pentaallyl ether ( 10) exhibited remarkable inhibitory effects on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test.

Anti-tumor promoting effects of multiflorane-type triterpenoids and cytotoxic activity of karounidiol against human cancer cell lines

Forty-nine multiflorane-type triterpenoids consisting of 11 compounds isolated from the seeds of Trichosanthes kirilowii (Cucurbitaceae) and 38 of their derivatives have been evaluated for their inhibitory effects on Epstein–Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12- O-tetradecanoylphorbol-13-acetate in Raji cells as a primary screening test for anti-tumor promoters. All of the compounds tested showed an inhibitory effect against EBV-EA activation, and among which 43 were revealed to possess remarkable activity with potencies either comparable to or stronger than that of glycyrrhetic acid, a known natural anti-tumor promoter. Their structure–activity relationship is discussed. Evaluation of the cytotoxic activity of karounidiol (27) against human cancer cell lines exhibited cytotoxicity especially against a human renal cancer.

Cancer chemopreventive agents, serratane-type triterpenoids from Picea jezoensis

Seven serratane-type triterpenoids isolated from the cuticle of Picea jezoensis (Sieb. et Zucc.) Carr. jezoensis (Pinaceae) and the stem bark of Picea jezoensis (Sieb. et Zucc.) Carr. hondoensis (Mayer) Rehder (Pinaceae) were studied their possible inhibitory effects on Epstein–Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). All compounds showed strong inhibitory effects on the EBV-EA activation, being stronger than that of oleanolic acid, which exerts on cancer preventive activity in animal carcinogenesis models. Among these compounds, 13α, 14α-epoxy-3β-methoxyserratan-21β-ol and 3β-methoxy-21α-hydroxyserrat-14-en-29-al were investigated for the inhibitory effects in a two-stage mouse skin carcinogenesis test on mouse skin using 7,12-dimethylbenz[a]anthracene as initiator and TPA as promoter. 13α,14α-Epoxy-3β-methoxyserratan-21β-ol was found to exhibit the excellent anti-tumor promoting activity in the in vivo carcinogenesis test.

New phenylpropanoid esters of sucrose from Polygonum lapathifolium.

Four new phenylpropanoid esters of sucrose, lapathosides A (1), B (2), C (3), and D (4), were isolated from the aerial parts of Polygonum lapathifolium together with known esters, vanicoside B (5) and hydropiperoside (6). The structures of 1-4 were determined by spectral (1D and 2D NMR and MS) analysis. Lapathoside A (1) and vanicoside B (2) showed significant inhibitory effects on the Epstein-Barr virus early antigen activation by tumor-promoters.

Diesters of glycosylglycerols active in cancer chemoprevention

Enzymatic transesterification, mediated by Pseudomonas cepacia lipase (lipase PS), led to the pure 1,6′-diacylderivatives of 2- O-β- d-glucosyl- sn-glycerol and 2- O-β- d-galactosyl- sn-glycerol, the acyl chains being derived from short-medium length fatty acids. A study of the in vitro inhibitory effects of these diacylderivatives on Epstein–Barr virus early antigen activation induced by the tumour promoter 12- O-tetradecanoylphorbol-13-acetate revealed that maximum activity was reached for the hexanoyl chain and that the introduction of a second acyl chain did not significantly modify the inhibitory potential referring to the corresponding 1- or 6′-monoesters.

Abietane diterpenoids from the cones of Larix kaempferi and their inhibitory effects on Epstein-Barr virus activation.

Four known (1-3, 8) and four new abietane diterpenes, 15-hydroxy-8alpha,14alpha,12alpha,13alpha-diepoxyabietan-18-oic acid (4), 7alpha,8alpha,13beta,14beta-diepoxyabietan-18-oic acid (5), 18-nor-abieta-8,11,13-triene-4alpha,7alpha,15-triol (6), and abieta-8,11,13-triene-7alpha,15,18-triol (7) were isolated from the CHCl3 extract of the cones of Larix koempferi. A known compound, 13,14-seco-13,14-dioxoabiet-13-en-18-oic acid (8) was isolated from natural sources for the first time. Their structures were determined by chemical and spectroscopic methods including 1D and 2D NMR techniques. The absolute stereostructure of 5 was determined by X-ray crystallographic analysis. The inhibitory effects of these compounds on Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), were examined as a primary screening for antitumor promotors.