Red ginseng and cancer treatment / 中国天然药物

The ginseng family, including Panax ginseng (Asian ginseng), Panax quinquefolius (American ginseng), and Panax notoginseng (notoginseng), is commonly used herbal medicine. White ginseng is prepared by air-drying after harvest, while red ginseng is prepared by a steaming or heating process. The anticancer activity of red ginseng is significantly increased, due to the production of active anticancer ginsenosides during the steaming treatment, compared with that of white ginseng. Thus far, anticancer studies have been mostly focused on Asian ginseng. In this article, we review the research progress made in the anticancer activities of red Asian ginseng, red American ginseng and red notoginseng. The major anticancer mechanisms of red ginseng compounds include cell cycle arrest, induction of apoptosis/paraptosis, and inhibition of angiogenesis. The structure-function relationship analysis has revealed that the protopanaxadiol group ginsenosides have more potent effects than the protopanaxatriol group. Sugar molecules in ginsenosides inversely impact the antiproliferative potential of these compounds. In addition, ginsenoside stereoselectivity and double bond position also influence the anticancer activity. Future studies should focus on characterizing active red ginseng derivatives as potential anticancer drugs.

Inhibition of Wnt Signaling by Silymarin in Human Colorectal Cancer Cells

Silymarin from milk thistle (Silybum marianum) has been reported to show an anti-cancer activity. In previous study, we reported that silymarin induces cyclin D1 proteasomal degradation through NF-κB-mediated threonine-286 phosphorylation. However, mechanism for the inhibition of Wnt signaling by silymarin still remains unanswered. Thus, we investigated whether silymarin affects Wnt signaling in human colorectal cancer cells to elucidate the additional anti-cancer mechanism of silymarin. Transient transfection with a TOP and FOP FLASH luciferase construct indicated that silymarin suppressed the transcriptional activity of β-catenin/TCF. Silymarin treatment resulted in a decrease of intracellular β-catenin protein but not mRNA. The inhibition of proteasome by MG132 and GSK3β inhibition by SB216763 blocked silymarin-mediated downregulation of β-catenin. In addition, silymarin increased phosphorylation of β-catenin and a point mutation of S33Y attenuated silymarin-mediated β-catenin downregulation. In addition, silymarin decreased TCF4 and increased Axin expression in both protein and mRNA level. From these results, we suggest that silymarin-mediated downregulation of β-catenin and TCF4 may result in the inhibition of Wnt signaling in human colorectal cancer cells.

Naringenin-Mediated ATF3 Expression Contributes to Apoptosis in Human Colon Cancer

Naringenin (NAR) as one of the flavonoids observed in grapefruit has been reported to exhibit an anti-cancer activity. Activating transcription factor 3 (ATF3) is associated with apoptosis in human colon cancer cells. This study was performed to investigate the molecular mechanism by which NAR stimulates ATF3 expression and apoptosis in human colon cancer cells. NAR reduced the cell viability and induced an apoptosis in human colon cancer cells. ATF3 overexpression increased NAR-mediated cleaved PARP, while ATF3 knockdown attenuated the cleavage of PARP by NAR. NAR increased ATF3 expression in both protein and mRNA level, and increased the luciferase activity of ATF3 promoter in a dose-dependent manner. The responsible region for ATF3 transcriptional activation by NAR is located between -317 and -148 of ATF3 promoter. p38 inhibition blocked NAR-mediated ATF3 expression, its promoter activation and apoptosis. The results suggest that NAR induces apoptosis through p38-dependent ATF3 activation in human colon cancer cells.

2-Methoxy-1,4-Naphthoquinone (MNQ) Suppresses Protein Kinase C βI, δ, and ζ Expression in Raji Cells.

Protein Kinase C (PKC) is widely documented to be involved in the regulation of cancer cell growth, proliferation, survival, inflammation and apoptosis. This study evaluates the capability of 2-Methoxy-1,4- Naphthoquinone (MNQ) in regulating PMA-induced PKC expression in human Burkitt’s lymphoma cell line (Raji cells). MNQ exhibited stronger anti-tumour-promoting activity than genistein based on the inhibitory assay of Epstein-Barr virus (EBV) activation. The IC50 values attained were 2.92 and 7.40 μM, respectively. The suppressive effects of MNQ on PKC expression was determined by using the PepTag® non-radioactive detection of PKC assay. The IC50 values achieved for staurosporine and rottlerin (standard control), and MNQ were 0.01, 6.38, and 13.13 μM, respectively. These preliminary results indicate that MNQ specifically suppressed the expression of PKC βI, δ, and ζ in a concentration-dependent manner in Raji cells.

Anti-Proliferative Effect of Naringenin through p38-Dependent Downregulation of Cyclin D1 in Human Colorectal Cancer Cells

Naringenin (NAR) as one of the flavonoids observed in grapefruit has been reported to exhibit an anti-cancer activity. However, more detailed mechanism by which NAR exerts anti-cancer properties still remains unanswered. Thus, in this study, we have shown that NAR down-regulates the level of cyclin D1 in human colorectal cancer cell lines, HCT116 and SW480. NAR inhibited the cell proliferation in HCT116 and SW480 cells and decreased the level of cyclin D1 protein. Inhibition of proteasomal degradation by MG132 blocked NAR-mediated cyclin D1 downregulation and the half-life of cyclin D1 was decreased in the cells treated with NAR. In addition, NAR increased the phosphorylation of cyclin D1 at threonine-286 and a point mutation of threonine-286 to alanine blocked cyclin D1 downregulation by NAR. p38 inactivation attenuated cyclin D1 downregulation by NAR. From these results, we suggest that NAR-mediated cyclin D1 downregulation may result from proteasomal degradation through p38 activation. The current study provides new mechanistic link between NAR, cyclin D1 downregulation and cell growth in human colorectal cancer cells.

A Study on the Useful Components of Adlay (<i>Coix lachryma-jobi</i> L. <i>var.ma-yuen</i> Stapf) / 日本補完代替医療学会誌

Hot water extract of adlay (<i>Coix lachryma-jobi</i> L. <i>var. ma-yuen</i> Stapf) seed, commonly called Yokuinin, has been used as herbal medicine for treating verruca vulgaris, et al. Although there have been a number of studies on the usefulness of Yokuinin, the pharmacological assessment of its husk, pellicle, and astringent skin remains unclear. In this line, we evaluated the effect of methanol extract from all parts of adlay grain (seed, husk, pellicle, astringent skin) on cancer cells and identified its useful chemical components. Results revealed that a fraction of the extract have weak growth-suppressing activity on human cervical cancer cell line (HeLa cell). In particular, 5,7-dihydroxychromone and coixol were isolated and identified from the active fraction. This indicates the possible cancer chemopreventive efficacy of methanol extract from adlay. Moreover, further tests are needed to determine the role of 5,7-dihydroxychromone.<br>

Capsaicin: A novel chemopreventive molecule and its underlying molecular mechanisms of action.

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is the a principal pungent ingredient of hot red and chili peppers that belong to the plant genus Capsicum (Solanaceae). Capsaicin is a cancer-suppressing agent. It blocks the translocation of nuclear factor kappa B (NF-kB), activator protein 1 (AP-1), and signal transducer and activator of transcription (STAT3) signaling pathway that are required for carcinogenesis. The anti-inflammatory potential of capsaicin is attributed to its inhibitory effect on inducible COX-2 mRNA expression. Cytochrome P4502E1 mediates the activation of xenobiotics such as vinyl carbamate and dimethyl nitrosamine to their toxic metabolites. This metabolic activation of xenobiotics by Cytochrome P4502E1 has been shown to be inhibited by capsaicin. Capsaicin also generates reactive oxygen species in cells with resultant induction of apoptosis and cell cycle arrest, which is beneficial for cancer chemoprevention. Therefore, the use of capsaicin as a chemopreventive agent is of immense benefit for cancer chemoprevention. The search strategy included printed journals, pubmed, and medline, using the terms 'capsaicin' and 'anticancer' citations, relevant to anticancer properties of capsaicin.

Chemoprevention with Dietary Plants: Promising Phytochemicals, Animal Model Studies and Possible Mechanisms of Action / 日本補完代替医療学会誌

Chemoprevention is currently regarded as one of the most promising avenues of cancer control. In the search for chemopreventive dietary plants and phytochemicals, the author has explored anti-tumor promotimg phytochemicals of vegetables and fruits in several Asian countries, using an inhibition test of tumor promoter-induced Epstein-Barr virus (EBV) activation. Extensive <i>in vitro</i> screening tests have found several dietary plants from subtropical zones to possess high potential. In particular, plants in families commonly ingested for purposes other than their nutritive value (<i>i.e.</i> as flavors, condiments, and occasionally traditional medicines) were shown to contain potent anti-tumor promoters. Of more than 50 <i>in vitro</i> anti-tumor promoters identified thus far, cancer preventive properties of 4 compounds from zingiberaceous (1′-acetoxychavicol acetate and zerumbone) and rutaceous (auraptene and nobiletin) plants have been further studied. The results of animal model experiments as well as modes of action, including anti-inflammation associated activities, are described. The present status of chemoprevention with food phytochemicals is also discussed.<br>

Cancer Chemoprevention by Food Components: Colon Cancer Chemoprevention by Seed Oils Rich in Conjugated Linolenic Acid / 日本補完代替医療学会誌

Cancer chemoprevention utilizing food components is attracted because of its easily availability in humans. Bitter melon (<i>Momordica charantia</i>) (BMO) and pomegranate (<i>Punica granatum</i> L.) (PGO) seed oils contain a large amount of conjugated linolenic acid (CLN). In the first we demonstrated that BMO inhibits the development of azoxymethane (AOM)-induced putative precursor lesions for colonic adenocarcinoma in rats. Subsequently, we investigated the modifying effects of dietary administration of BMO or PGO on the development of colonic neoplasms using an animal colon carcinogenesis model initiated with a colon carcinogen AOM. Male F344 rats were given two weekly subcutaneous injections of AOM (20 mg/kg body weight) to induce colonic neoplasms. They were fed with the diets containing 0.01%, 0.1% and 1% BMO or PGO during the entire experimental period (for 32 weeks), starting one week before the first dosing of AOM. At the end of the study, the incidence and multiplicity of colonic adenocarcinoma were reduced in the "AOM+BMO" and "AOM+PGO" groups, when compared with the "gAOM alone" group. The contents of conjugated linoleic acid (CLA: 9<i>c</i>,11<i>t</i>-18:2) in the liver and colonic mucosa of rats fed BMO or PGO were elevated in a dose-dependent manner. Also, dietary BMO or PGO enhanced expression of peroxisome proliferator-activated receptor (PPAR)γ protein in the colonic mucosa. These findings may suggest that BMO or PGO rich in CLN can suppress AOM-induced colon carcinogenesis through the modification of lipid composition in the colon and liver and/or increased expression of PPARγ protein level in the colon mucosa. Our results might provide scientific evidence of an effective dietary chemopreventive approach using BMO and PGO seed oils rich in CLN to cancer chemoprevention, especially colon cancer development.<br>

Cancer Chemoprevention by Ginseng in Mouse Liver and Other Organs

Oral administration of red ginseng extracts (1% in diet for 40 weeks) resulted in the significant suppression of spontaneous liver tumor formation in C3H/He male mice. Average number of tumors per mouse in control group was 1.06, while that in red ginseng extracts-treated group was 0.33 (p<0.05). Incidence of liver tumor development was also lower in red ginseng extracts-treated group, although the difference from control group was not statistically significant. Anti-carcinogenic activity of white ginseng extracts, besides red ginseng extracts, was also investigated. In the present study, the administration of white ginseng extracts was proven to suppress tumor promoter-induced phenomena in vitro and in vivo. It is of interest that oral administration of the extracts of Ren-Shen-Yang- Rong-Tang, a white ginseng-containing Chinese medicinal prescription, resulted in the suppression of skin tumor promotion by 12-o-tetradecanoylphorbol-13-acetate in 7,12-dimethylbenz[a]anthracene-initiated CD-1 mice. These results suggest the usefulness of ginseng in the field of cancer prevention.