Oxidative metabolites of lycopene and γ-carotene in gac (Momordica cochinchinensis).

Three new oxidative metabolites of lycopenes, (erythro)-lycopene-5,6-diol, (threo)-lycopene-5,6-diol, and 1,16-dehydro-2,6-cyclolycopene-5-ol B, and four new oxidative metabolites of γ-carotenes, 2',6'-cyclo-γ-carotene-1',5'-diol A, 2',6'-cyclo-γ-carotene-1',5'-diol B, (erythro)-γ-carotene-5,6-diol, and (threo)-γ-carotene-5,6-diol, were isolated as minor components from the aril of gac, Momordica cochinchinensis. These structures were determined on the basis of spectroscopic data, and some of them were compared to the structures of synthetic samples. Furthermore, the oxidative metabolic conversion pathways of lycopene and γ-carotene were discussed.

Phytochemicals in hepatocellular cancer prevention.

Since the incidence of liver cancer is increasing in the world, it is valuable to develop an effective method for its prevention. Various phytochemicals have been shown to suppress liver carcinogenesis in experimental studies. Using these phytochemicals, a clinical trial was conducted. Combination of carotenoids and myo-inositol was found to prevent hepatocellular carcinoma development in patients with chronic viral hepatitis and cirrhosis.

Anticarcinogenic compounds in the Uzbek medicinal plant, Helichrysum maracandicum.

An ethanol extract of Helichrysum maracandicum showed antiproliferative activity against cultured cells of SENCAR mouse in an in vitro assay, and activity-guided fractionation of the extract resulted in the isolation of isosalipurposide as an active substance. Naringenin chalcone, the aglycone of isosalipurposide, also showed strong antiproliferative activity. An in vivo assay of two-stage carcinogenesis on mouse skin revealed that epidermal application of isosalipurposide resulted in delayed formation of papillomas. Western blot analysis showed that the expression of p38 mitogen-activated protein kinase was suppressed by the administration of naringenin chalcone or isosalipurposide, which might be related to the anticarcinogenic activity.

Cancer control by phytochemicals.

Chemoprevention is one of the most important strategy in the field of cancer control. Molecular mechanism-based cancer chemoprevention by phytochemicals seems to be very attractive method. In this review, possible molecular targets for cancer prevention are overviewed, and some examples of cancer preventive phytochemicals, such as carotenoids, are presented.

Cucurbitane-type triterpenoids from the fruits of Momordica charantia and their cancer chemopreventive effects.

Thirteen cucurbitane-type triterpene glycosides, including eight new compounds named charantosides I (6), II (7), III (10), IV (11), V (12), VI (13), VII (16), and VIII (17), and five known compounds, 8, 9, 14, 15, and 18, were isolated from a methanol extract of the fruits of Japanese Momordica charantia. The structures of the new compounds were determined on the basis of spectroscopic methods. On evaluation of these triterpene glycosides and five other cucurbitane-type triterpenes, 1-5, also isolated from the extract of M. charantia fruits, for their inhibitory effects on the induction of Epstein-Barr virus early antigen (EBV-EA) by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells, these compounds showed inhibitory effects on EBV-EA induction with IC(50) values of 200-409 mol ratio/32 pmol TPA. In addition, upon evaluation of compounds 1-5 for inhibitory effects against activation of (+/-)-(E)-methyl-2[(E)-hydroxyimino]-5-nitro-6-methoxy-3-hexemide (NOR 1), a nitrogen oxide (NO) donor, compounds 1-3 showed moderate inhibitory effects. Compounds 1 and 2 exhibited marked inhibitory effects in both 7,12-dimethylbenz[a]anthracene (DMBA)- and peroxynitrite (ONOO-; PN)-induced mouse skin carcinogenesis tests.

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. The authors here report that sesamin induces growth arrest at the G1 phase in cell cycle progression in the human breast cancer cell line MCF-7. Furthermore, sesamin dephosphorylates tumor-suppressor retinoblastoma protein (RB). It is also shown that inhibition of MCF-7 cell proliferation by sesamin is correlated with down-regulated cyclin D1 protein expression, a proto-oncogene that is overexpressed in many human cancer cells. It was found that sesamin-induced down-regulation of cyclin D1 was inhibited by proteasome inhibitors, suggesting that sesamin suppresses cyclin D1 protein expression by promoting proteasome degradation of cyclin D1 protein. Sesamin down-regulates cyclin D1 protein expression in various kinds of human tumor cells, including lung cancer, transformed renal cells, immortalized keratinocyte, melanoma and osteosarcoma. Furthermore, depletion of cyclin D1 protein using small interfering RNA rendered MCF-7 cells insensitive to the growth inhibitory effects of sesamin, implicating that cyclin D1 is at least partially related to the antiproliferative effects of sesamin. Taken together, these results suggest that the ability of sesamin to down-regulate cyclin D1 protein expression through the activation of proteasome degradation could be one of the mechanisms of the antiproliferative activity of this agent.

Triterpene acids from Poria cocos and their anti-tumor-promoting effects.

The structures of six new lanostane-type triterpene acids isolated from the epidermis of the sclerotia of Poria cocos were established to be 15alpha-hydroxydehydrotumulosic acid (5), 16alpha,25-dihydroxydehydroeburicoic acid (9), 5alpha,8alpha-peroxydehydrotumulosic acid (10), 25-hydroxyporicoic acid H (11), 16-deoxyporicoic acid B (12), and poricoic acid CM (16) on the basis of spectroscopic methods. On evaluation of these six and 11 other known triterpene acids isolated from the sclerotium, 1-4, 6-8, 13-15, and 17, against the Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells, all of the compounds except for 1, 3, 4, and 8 exhibited inhibitory effects with IC50 values of 195-340 mol ratio/32 pmol TPA. Compound 12 and poricoic acid C (13) exhibited inhibitory effects on skin tumor promotion in an in vivo two-stage carcinogenesis test using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter.

Aged garlic extract prevents a decline of NK cell number and activity in patients with advanced cancer.

Aged garlic extract (AGE) has manifold biological activities including immunomodulative and antioxidative effects. It is used as a major component of nonprescription tonics and cold-prevention medicines or dietary supplements. Advanced-cancer patients decline in immune functions and quality of life (QOL). The study's subjects were patients with inoperable colorectal, liver, or pancreatic cancer. In a randomized double-blind trial, AGE was administered to one group and a placebo was administered to another for 6 mo. The primary endpoint was a QOL questionnaire based on the Functional Assessment of Cancer Therapy (FACT). The subendpoints were changes in the natural-killer (NK) cell activity the salivary cortisol level from before and after administering AGE. Out of 55 patients invited to participate in the trial, 50 (91%) consented to enroll. They consisted of 42 patients with liver cancer (84%), 7 patients with pancreatic cancer (14%), and 1 patient with colon cancer (2%). Drug compliance was relatively good in both the AGE and placebo groups. Although no difference was observed in QOL, both the number of NK cells and the NK cell activity increased significantly in the AGE group. No adverse effect was observed in either group. The study showed that administering AGE to patients with advanced cancer of the digestive system improved NK cell activity, but caused no improvement in QOL.

Chalcones and other compounds from the exudates of Angelica keiskei and their cancer chemopreventive effects.

Three new chalcones, xanthoangelol I (1), xanthoangelol J (2), and deoxydihydroxanthoangelol H (3), were isolated from an ethyl acetate-soluble fraction of exudates of the stems of Angelica keiskei, and their structures were established on the basis of spectroscopic methods. Nine aromatic compounds of known structure, 4-12, and a diacetylene, 13, were also isolated and identified from this same fraction. On evaluation of these compounds for their inhibitory effects on the induction of Epstein-Barr virus early antigen (EBV-EA) by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells, 1, 2, 4, and 9-12 showed potent inhibitory effects on EBV-EA induction. In addition, upon evaluation of the inhibitory effects against activation of (+/-)-(E)-methyl-2[(E)-hydroxyimino]-5-nitro-6-methoxy-3-hexemide (NOR 1), a nitrogen oxide (NO) donor, six compounds, namely, 1, 2, 4, 9, 11, and 12, exhibited potent inhibitory effects. Further, isobavachalcone (4) exhibited inhibitory effects on skin tumor promotion in an in vivo two-stage mouse skin carcinogenesis test using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter.

Antitumor-promoting activity of coumarins from citrus plants.

In order to identify antitumor-promoting agents, we performed primary in vitro screening of 31 coumarins isolated from 11 plants of the Citrus species (Rutaceae), examining their possible inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12- O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Some of the 8-substituted coumarins, 8-formyl-7-hydroxycoumarin (5), osthenol (7), demethylauraptenol (8), osthenon (9) and dihydroosthenon (10), were found to significantly inhibit EBV-EA activation (IC50: 129-207 mol ratio/32 pmol TPA). Osthenol (7) exhibited a marked inhibitory effect on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test.

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. These findings suggest that compound 1 may be valuable as potential cancer chemopreventive agent in chemical and environmental carcinogenesis.

Chemical constituents of Glycosmis arborea: three new carbazole alkaloids and their biological activity.

As part of the phytochemical studies of the plant genus Glycosmis, the constituents of the plant Glycosmis arborea were investigated. Three new carbazole alkaloids named glybomines A (1), B (2), and C (3), along with known monomeric alkaloids belonging to the carbazole, quinazoline, furoquinoline, quinolone, and acridone classes, were isolated from stems of the plant collected at Mymensing in Dhaka, Bangladesh. Glybomine A (1) is the first example of a 2,5-oxygenated carbazole alkaloid from natural sources. As a primary screening test for anti-tumor promoters, nine alkaloids isolated from this plant have been tested for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) induction by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). All alkaloids tested showed inhibitory activity.

Cancer chemopreventive activity of phenylpropanoids and phytoquinoids from Illicium plants.

In our joint project involving search of anti-tumor promoters from natural plant sources, six phenylpropanoids and seven phytoquinoids isolated from three Illicium plants (Illiciaceae) were tested for their inhibitory activities against Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate in Raji cells. All tested compounds showed inhibitory activity against the EBV-EA activation even at 1 x 10mol ratio, and the inhibitory activity of their compounds was found to be more than that of beta-carotene. Two phenylpropanoids having prenyl group, 4-allyl-2-methoxy-6-(3-methyl-2-butenyl)phenol (3) and 4-allyl-2,6-dimethoxy-3-(3-methyl-2-butenyl)phenol (4), showed more potent activities as anti-tumor promoters (IC50 224 and 217 mol ratio/TPA, respectively). The presence of a prenyl moiety in the phenylpropanoids plays an important role in anti-tumor promoting activity as xanthone, coumarin and flavonoid previously reported. This investigation indicated that prenylated phenylpropanoids might be valuable as potential cancer chemopreventive agents.

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. The inhibitory activity of 3 was found to be equivalent to that of beta-carotene without any cytotoxicity. Deguelin ( 4) and alpha-toxicarol ( 5) exhibited a marked inhibitory effect on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test. This investigation indicated that rotenoids might be valuable anti-tumor promoters.

Chemical constituents of Millettia taiwaniana: structure elucidation of five new isoflavonoids and their cancer chemopreventive activity.

We describe the isolation and identification of five new isoflavonoids, millewanins A (1), B (2), C (3), D (4), and E (5), together with six known isoflavonoids and three rotenoids, from the stems of Millettia taiwaniana collected in Japan. The major component, auriculasin (6), exhibited significant inhibitory effect on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test. The results of the present investigation indicate that 6 might be a valuable antitumor promoter.

Activation of protein kinase C promotes human cancer cell growth through downregulation of p18(INK4c).

p18(INK4c), a member of INK4 family of cyclin-dependent kinase inhibitors, negatively regulates the cyclin D-cyclin-dependent kinase 4/6 complexes which promote G1/S transition by phosphorylating the retinoblastoma tumor-suppressor gene product. Several recent studies using p18(INK4c)-null mice revealed that the p18(INK4c) plays an important role in cell proliferation and tumor development. We report here that 12-O-tetradecanoylphorbol-13-acetate (TPA), widely used as a protein kinase C (PKC) activator, suppresses the expression of p18(INK4c) through its promoter, accompanied by the induction of human cancer cell growth. Reduction of p18(INK4c) using small interfering RNA (siRNA) also enhanced cell growth, suggesting that p18(INK4c) is a critical target of TPA. Ro 31-8425, a potent and highly specific PKC inhibitor abrogated the suppressive effect of TPA on p18(INK4c) gene expression. However, the expression of dominant-negative c-Jun (TAM-67) did not inhibit the action of TPA on p18(INK4c). These findings suggest that activation of PKC promotes human cancer cell growth through downregulation of p18(INK4c) in an AP-1 activation-independent manner. These results suggest that the accelerated cellular proliferation of some human tumors caused by enhanced PKC activity at least partially involves the suppression of p18(INK4c), which is a ubiquitously expressed cyclin-dependent kinase inhibitor.

Dimeric flavonol glycoside and galloylated C-glucosylchromones from Kunzea ambigua.

A novel dimeric flavonol glycoside linked through a methylene group, kunzeagin A (1), and six new chromone C-glucosides, kunzeachromones A-F (2-7), were isolated along with seven known compounds from the leaf extract of Kunzea ambigua. The structures of these compounds were elucidated on the basis of spectroscopic analyses and chemical properties. Kunzeachromones A-F provided additional examples of galloylated C-glucosidic chromones occurring in the Myrtaceae. Kunzeagin A (1) and major constituents of this plant (6-C- and 8-C-glucosylchromones and their monogallates) exhibited potent inhibitory effects on activation of Epstein-Barr virus early antigen induced by 12-O-tetradecanoylphorbol 13-acetate 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. The inhibitory activity of 3 was found to be equivalent to that of beta-carotene without any cytotoxicity. Deguelin ( 4) and alpha-toxicarol ( 5) exhibited a marked inhibitory effect on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test. This investigation indicated that rotenoids might be valuable anti-tumor promoters.

Triterpene acids from the leaves of Perilla frutescens and their anti-inflammatory and antitumor-promoting effects.

Nine triterpene acids, viz., six of the ursane type, ursolic acid (1), corosolic acid (2), 3-epicorosolic acid (3), pomolic acid (4), tormentic acid (5) and hyptadienic acid (6), and three of the oleanane type, oleanolic acid (7), augustic acid (8) and 3-epimaslinic acid (9), among which 1 constituted the most predominant triterpene acid, were isolated and identified from ethanol extracts of the leaves of red perilla [Perilla frutescens (L.) Britton var. acuta Kudo] and green perilla [P. frutescens (L.) Britton var. acuta Kudo forma viridis Makino]. These eight compounds, 1, 2, 4-9, were evaluated for their inhibitory effects on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation (1 microg/ear) in mice. All the compounds tested showed a marked anti-inflammatory effect, with a 50% inhibitory dose (ID50) of 0.09-0.3 mg per ear. In addition, an evaluation against the Epstein-Barr virus early antigen (EBV-EA) activation induced by TPA showed five compounds, 1-3, 5 and 9, with a potent inhibitory effect on EBV-EA induction (91-93% inhibition at 1x10(3) mol ratio/TPA). Furthermore, compound 5 exhibited strong antitumor-promoting activity in an in vivo two-stage carcinogenesis test of mouse tumor by using 7,12-dimethylbenz(a)anthracene (DMBA) as an initiator and TPA as a promoter.

3-epicabraleahydroxylactone and other triterpenoids from camellia oil and their inhibitory effects on Epstein-Barr virus activation.

The structure of a triterpenoid isolated from the nonsaponifiable lipid (NSL) of the seed oil of the camellia (Camellia japonica L.; Theaceae) was established to be (20S)-3beta-hydroxy-25,26,27-trisnordammaran-24,20-olide (1; 3-epicabraleahydroxylactone) on the basis of spectroscopic and chemical methods. Six other triterpenoids isolated from the NSL were identified as 3-epicabraleadiol (2), ocotillol II (3), ocotillol I (4), dammarenediol II (5), (20R)-taraxastane-3beta,20-diol (6), and lupane-3beta,20-diol (7). Upon evaluation of the seven triterpenoids (1-7) with respect to their inhibitory effects on the induction of Epstein-Barr virus early antigen (EBV-EA) by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells, three compounds (5-7) showed potent inhibitory effects against EBV-EA induction (IC(50) values of 277-420 mol ratio/32 pmol TPA).