Cancer preventive agents. Part 8: Chemopreventive effects of stevioside and related compounds.

In a search for potential cancer chemopreventive agents from natural resources, stevioside (1), a sweetener, and six related compounds, including two aglycones steviol (6) and isosteviol (7), were screened in an in vitro assay for inhibitory effects on Epstein-Barr virus early antigen activation. Compounds 1, 6 and 7 showed significant activity in this assay and also exhibited strong inhibitory effects in a two-stage carcinogenesis test using mouse skin induced by 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). The inhibitory effects of these three compounds were greater than that of glycyrrhizin.

New isoflavone glycosides from Iris spuria L. (Calizona) cultivated in Egypt.

Two new isoflavone glycosides, tectorigenin 7-O-beta-D-glucopyranoside-4'-O-[beta-D-glucopyranosyl-(1''''-->6''')-beta-D-glucopyranoside] (1) and iristectorigenin B 4'-O-[beta-D-glucopyranosyl-(1'' --> 6'')-beta-D-glucopyranoside] (2), together with 11 known compounds, including six isoflavones, tectorigenin 7-O-beta-D-glucopyranoside-4'-O-beta-D-glucopyranoside (3), tectorigenin 4'-O-[beta-D-glucopyranosyl-(1'''--> 6'')-beta-D-glucopyranoside] (4), tectorigenin 7-O-beta-D-glucopyranoside (5), genistein 7-O-beta-D-glucopyranoside (6), tectorigenin 4'-O-beta-D-glucopyranoside (7), and tectorigenin (8); two phenolic acid glycosides, vanillic acid 4-O-beta-D-glucopyranoside (9) and glucosyringic acid (10); a phenylpropanoid glycoside, E-coniferin (11); an auronol derivative, maesopsin 6-O-beta-D-glucopyranoside (12); and a pyrrole derivative, 4-(2-formyl-5-hydroxymethylpyrrol-1-yl) butyric acid (13), were isolated from fresh Iris spuria (Calizona) rhizomes. The structures of these compounds were established on the basis of spectroscopic and chemical evidence. Inhibitory effects on the activation of Epstein-Barr virus early antigen were examined for compounds 1-8 and 12.

Sesamin, a lignan of sesame, down-regulates cyclin D1 protein expression in human tumor cells.

Sesamin is a major lignan constituent of sesame and possesses multiple functions such as antihypertensive, cholesterol-lowering, lipid-lowering and anticancer activities. Several groups have previously reported that sesamin induces growth inhibition in human cancer cells. However, the nature of this growth inhibitory mechanism remains unknown.

Anti-tumor-initiating effects of monascin, an azaphilonoid pigment from the extract of Monascus pilosus fermented rice (red-mold rice).

Monascin (1) constitutes one of the azaphilonoid pigments in the extracts of Monascus pilosus-fermented rice (red-mold rice). Compound 1 was evaluated for its anti-tumor-initiating activity via oral administration on the two-stage carcinogenesis of mouse skin tumor induced by peroxynitrite (ONOO-; PN) or by ultraviolet light B (UVB) as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoter. Compound 1 exhibited marked inhibitory activity on both PN- and UVB-induced mouse skin carcinogenesis tests.

Cyclic and branched acyl chain galactoglycerolipids and their effect on anti-tumor-promoting activity.

Fifteen new galactoglycerolipid analogues, in which one or two branched, alicyclic or aromatic acyl chains are linked to 2-O-beta-D-galactosylglycerol (6'-position or 1,6' positions), were prepared and tested for their anti-tumor-promoting activity using a short-term in vitro assay for Epstein-Barr virus early antigen (EBV-EA) activation. All compounds were active in inhibiting the EBV activation promoted by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), the branched compounds resulting in the most active glycoglycerolipid analogues of the series. The branched 2-O-[6-O-(3-methylbutanoyl)-beta-D-galactopyranosyl]-sn-glycerol (1a) and the structurally related alicyclic 2-O-[6-O-(2-cyclohexylethanoyl)-beta-D-galactopyranosyl]-sn-glycerol (1d), when tested in an in vivo two-stage carcinogenesis test, exhibited inhibitory effects on mouse skin tumor promotion.

Cancer prevention by antioxidants.

Various antioxidants in foods, such as phenolic compounds and carotenoids, were proven to have anticarcinogenic activity. In the case of carotenoids, the mixture of them was found to be very effective. In fact, the development of hepatoma in the high risk group of liver cancer, was significantly suppressed by the treatment with natural carotenoids mixture.

Correlation of redox potentials and inhibitory effects on Epstein-Barr virus activation of 2-azaanthraquinones.

As a continuation of our studies using natural and synthetic products as cancer chemopreventive agents, we examined the standard redox potentials of some 2-azaanthraquinones in phosphate buffer at pH 7.2 by means of cyclic voltammetry. A definite correlation has been found between the redox potentials and the inhibitory effects of the 2-azaanthraquinones on Epstein-Barr virus early antigen (EBV-EA) activation.

Cancer chemopreventive activity of rotenoids from Derris trifoliata.

A study of the chemical constituents of the stems of Derris trifoliata Lour. (Leguminosae) led to the isolation and identification of one new rotenoid, 6aalpha,12aalpha-12a-hydroxyelliptone ( 3), together with five other known rotenoids. In a search for novel cancer chemopreventive agents (anti-tumor promoters), we carried out a primary screening of five of the rotenoids isolated from the plant for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12- O-tetradecanoylphorbol 13-acetate (TPA) in Raji cells.

Cancer chemopreventive activity of rotenoids from Derris trifoliata.

A study of the chemical constituents of the stems of Derris trifoliata Lour. (Leguminosae) led to the isolation and identification of one new rotenoid, 6aalpha,12aalpha-12a-hydroxyelliptone ( 3), together with five other known rotenoids. In a search for novel cancer chemopreventive agents (anti-tumor promoters), we carried out a primary screening of five of the rotenoids isolated from the plant for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12- O-tetradecanoylphorbol 13-acetate (TPA) in Raji cells.

Cancer chemopreventive effect of phenothiazines and related tri-heterocyclic analogues in the 12-O-tetradecanoylphorbol-13-acetate promoted Epstein-Barr virus early antigen activation and the mouse skin two-stage carcinogenesis models.

In continuation of our search for novel agents, we have investigated 29 phenothiazines and related tri-heterocyclic compounds as potential cancer chemopreventive agents in a short-term in vitro assay of Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Among the evaluated compounds, chlorpromazine, phenoxazine, ethylpropazine, 9-oxo-9H-thioxanthene-3-carbonitrile-10,10-dioxide, thiothixene and phenothiazine showed profound inhibition of EBV-EA in the in vitro assay. This activity was influenced by a modification of the phenothiazine ring.

Correlation of redox potentials and inhibitory effects on Epstein-Barr virus activation of naphthoquinones.

As a continuation of our studies using natural and synthetic products as cancer chemopreventive agents, we examined the standard redox potentials of some naphthoquinones in phosphate buffer at pH 7.2 by means of cyclic voltammetry. A definite correlation has been found between the redox potentials and the inhibitory effects of the naphthoquinones on Epstein-Barr virus early antigen activation.

Cancer chemopreventive effects of oral feeding alpha-tocopherol on ultraviolet light B induced photocarcinogenesis of hairless mouse.

Ultraviolet light is the most common cause of skin cancers in humans and several effects of ultraviolet light B (UVB: 290-320 nm) are thought to contribute to skin photocarcinogenesis. The generation of free radicals and related oxidants produced by UVB exposure, result in photocarcinogenesis by directly damaging DNA. On the other side, activating of transcription factor, activator protein 1 (AP-1) induced by UVB exposure causes tumor promotion.

Isolation, structural elucidation, and inhibitory effects of terpenoid and lipid constituents from sunflower pollen on Epstein-Barr virus early antigen induced by tumor promoter, TPA.

Eight fatty acid esters of triterpene alcohols (1-8), four free triterpene alcohols (9, 12, 17, and 18), four diterpene acids (19-22), two tocopherol-related compounds (23 and 24), four estolides (25-28), three syn-alkane-4,6-diols (29-31), one 1,3-dioxoalkanoic acid (32), and one aliphatic ketone (33), along with the mixture of free fatty acids, were isolated from the diethyl ether extract of the pollen grains of sunflower (Helianthus annuus). Among these compounds, 14 (2-8, 12, 23, 25-28, and 33) were new naturally occurring compounds, and their structures were determined on the basis of spectroscopic methods. Twenty-four terpenoids and lipids (1-4, 6-9, 12, and 19-33) and six free triterpene triols (10, 11, and 13-16), derived from their fatty acid esters (2, 3, and 5-8) by alkaline hydrolysis, were evaluated with respect to their inhibitory effects on the induction of Epstein-Barr virus early antigen (EBV-EA) induced by the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), in Raji cells, which is known to be a primary screening test for antitumor promoters.

Cancer Chemoprevention by Phytochemicals and their Related Compounds.

Cancer chemoprevention by phytochemicals may be one of the most feasible approaches for cancer control. For example, phytochemicals obtained from vegetables, fruits, spices, teas, herbs and medicinal plants, such as carotenoids, phenolic compounds and terpenoids, have been proven to suppress experimental carcinogenesis in various organs. These candidates should be evaluated by intervention studies, before acceptance as cancer preventive agents for human application.

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.

Antitumor agents 220. Antitumor-promoting effects of cimigenol and related compounds on Epstein-Barr virus activation and two-stage mouse skin carcinogenesis.

Cimigenol (1) and 39 related compounds were screened as potential antitumor promoters by examining the ability of the compounds to inhibit Epstein-Barr virus early antigen (EBV-EA) activation (induced by 12-O-tetradecanoylphorbol-13-acetate) in Raji cells. Structure-activity relationship analysis indicated that compound 1 showed the highest activity and also exhibited significant inhibitory effects on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test. These data suggest that 1 and the related compounds might be valuable anti-tumor promoters.

Inhibitory effect of stabilized analogues of glycoglycerolipids on Epstein-Barr virus activation and mouse skin tumor promotion.

Nine new synthetic compounds, structurally related to the most active glycoglycerolipid analogues carrying a hexanoyl chain, were tested for their anti-tumor-promoting activity using a short-term in vitro assay for Epstein-Barr virus (EBV) activation. All these compounds, in which the ester function is replaced by different metabolically more stable groups, were almost as active as their ester reference compounds in inhibiting the EBV activation promoted by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Two of these, devoid of any functionality on the lipophilic chain, when tested in an in vivo two-stage carcinogenesis test, exhibited marked inhibitory effects on mouse skin tumor promotion.

Cancer chemopreventive effects of a Brazilian folk medicine, Juca, on in vivo two-stage skin carcinogenesis.

Gallic acid (1) and methyl gallate (2) were isolated from Juca, a Brazilian folk medicine, fruits of Caesalpinia ferrea MART (Leguminosae), decreased significantly the average number of papillomas per mouse in the experiment of the promoting effects of 12-O-tetra- decanoylphorbol-13-acetate (TPA) on skin tumor formation in mice initiated with 7,12-dimethylbenz[a]anthracene (DMBA).