Key words: prostate cancer; evodiamine; cell growth; G2/M arrest; apoptosisProstate cancer is the most commonly diagnosed malignancy in American men over 40 years of age and is the second leading of cancer deaths. 1,2 Recently, prostate cancer has become more and more common in Asia including Taiwan. 3 According to previous studies, widely accepted risk factors for prostate cancer are age, race, ethnicity, dietary habits, androgen production and metabolism. 4 Prostate cancer is characterized by an initial androgen dependency in which the growth of cancer is enhanced by androgen. 5 In this stage, treatment is aimed at either lowering the plasma level of testosterone or inhibiting its biological effects or those of its metabolites at the target tissue levels. Orchidectomy, LHRH agonists and antiandrogenic drugs have been used clinically for treatment of androgen-dependent prostate cancer. 6 -8 However, these therapies cause psychological and physiological side effects. 9 -11 The drugs for androgen-dependent prostate cancer have merits and limitations. Because of the side effects and limitations of the currently available treatments, there is a need to identify and develop new antitumor agents against androgen-dependent prostate cancer.It has been demonstrated that several microchemicals that are isolated from herbs and plants with diversified pharmacological properties exert inhibitory effects on the proliferation of cancer. [12][13][14][15][16] The microchemicals could be the most desirable agents for prevention or intervention of human cancer incidence and mortality due to stomach, colon, breast, esophagus, lung, bladder and even prostate carcinoma. [17][18][19] Our previous studies showed that cardiac glycosides from digitalis and Chansu exhibited the antiproliferative effects on prostate cancer cells including DU145, PC3 and LNCaP to mediate the elevated [Ca2 ϩ ] i and apoptosis. 19,20 Wu-Chu-Yu is a long-standing Chinese herb used for syndromes characterized by cold hands and gastrointestinal disorders. Evodiamine is one of the major bioactive compounds isolated and purified from Wu-Chu-Yu. It has been demonstrated that evodiamine influences many physiological functions including vasotension, anoxia and body temperature. [21][22][23] Meanwhile, evodiamine exhibits an anti-inflammatory effect on change of nitric oxide production in murine macrophage. 24 Recently, we found that evodiamine inhibited testosterone production via a decrease of 17␤-hydroxysteroid dehydrogenase activity in testicular interstitial cells. 25 Interestingly, the evidence showed that rutaecarpine, the other bioactive compound isolated from Wu-Chu-Yu, inhibited the growth of many kinds of cancers including breast, lung and kidney cancers. 26 Furthermore, Okasawara et al. 27,28 reported that evodiamine inhibited the cell proliferation, cell migration and lung metastasis of murine colon cancer cells.According to previous reports, evodiamine has been recognized as a compound for anti-metastatic and anti-tumor agent in colon cancer cells. It w...

From the ethanolic extract of Dichrocephala bicolor eight compounds-4,5-dicaffeoyl quinic acid (1); 3,4-dicaffeoyl quinic acid (2); 3,5-dicaffeoyl quinic acid (3); ethyl 4,5-dicaffeoyl quinate (4); methyl 3,5-dicaffeoyl quinate (5); 5-caffeoyl quinic acid (6); caffeic acid (7); and quercetin-3-O-rutinoside (8)-were isolated and identified. All of them were selected for immunopharmacological activity testing. Human mononuclear cells (HMNC) were used as target cells. Cell proliferation was determined by 3H-thymidine uptake. Compounds 2 and 6 potently enhanced HMNC proliferation and interferon-gamma production. Enhancement mechanisms may involve the increase of cytokines production.

Four new biflavonoids-robustaflavone 4'-methyl ether (1), robustaflavone 7,4'-dimethyl ether (2), 2",3" -dihydrorobustaflavone 7,4', -dimethyl ether (3), and 2",3" '-dihydrorobustaflavone 7,4', 7"-trimethyl ether (4)-as well as two known biflavonoids, robustaflavone and amentoflavone, and three caffeoylquinic acids, 3,5-di-O-caffeoylquinic acid, 3, 4-di-O-caffeoylquinic acid, and 4,5-di-O-caffeoylquinic acid, were isolated from Selaginella delicatula. The structures of the new compounds were established by spectroscopic analysis and chemical modification. The cytotoxic activity of these compounds on various tumor cell lines was evaluated, and both compounds 1 and 3 significantly suppressed the growth of Raji and Calu-1 tumor cell lines.

Purpose: It is important to identify the definitive molecular switches involved in the malignant transformation of premalignant tissues. Cellular senescence is a specific characteristic of precancerous tissues, but not of cancers, which might reflect tumorigenesis-protecting mechanisms in premalignant lesions. Polycomb protein Bmi1, which is a potent negative regulator of the p16INK4 gene, suppresses senescence in primary cells and is overexpressed in various cancers. We hypothesized that Bmi1 expression would also be dysregulated in precancerous lesions in human digestive precancerous tissues. Experimental Design: Bmi1 expression was investigated in cancerous and precancerous tissues of the digestive tract. The expression of p16, h-catenin, and Gli1 and the in vivo methylation status of the p16 gene were also analyzed in serial sections of colonic precancerous lesions. Results: Bmi1 was clearly overexpressed across a broad spectrum of gastrointestinal cancers, and the expression of Bmi1 increased in a manner that reflected the pathologic malignant features of precancerous colonic tissues (low-grade dysplasia, 12.9 F 2.0%; high-grade dysplasia, 82.9 F 1.6%; cancer, 87.5 F 2.4%). p16 was also strongly expressed in high-grade dysplasia, but not in cancers. p16 promoter methylation was detected only in some Bmi1-positive neoplastic cells. Conclusions: Bmi1overexpression was correlated with the malignant grades of human digestive precancerous tissues, which suggests that advanced Bmi1dysregulation might predict malignant progression. The abnormal Bmi1 expression might link to malignant transformation via the disturbance of orderly histone modification.

Effects of piperlactam S (C(17)H(13)NO(4); mol. wt. 295) isolated from Piper kadsura on phytohemagglutinin (PHA) stimulated cell proliferation were studied in primary culture of human T cells. The results showed that piperlactam S suppressed T cell proliferation at about 0 to 12 h after stimulation with PHA. Synthesis of total cellular proteins and RNA in activated cell cultures was also suppressed. The inhibitory action of piperlactam S was not through direct cytotoxicity. Cell cycle analysis indicated that piperlactam S arrested the cell cycle progression of activated T cells from the G(1) transition to the S phase. In an attempt to further localize the point in the cell cycle at which arrest occurred, a set of key regulatory events leading to the G(1)/S boundary, including gene expression of cytokines and c-Fos protein synthesis, was examined. Piperlactam S suppressed, in activated T lymphocytes, the production and mRNA expression of cytokines such as interleukin-2 (IL-2), IL-4, and interferon-gamma in a dose-dependent manner. In addition, Western blot analysis indicated that c-Fos protein expressed in activated T lymphocytes was decreased by piperlactam S. Results of kinetic study indicated that inhibitory effects of piperlactam S on IL-2 mRNA expressed in T cells might be related to blocking c-Fos protein synthesis. Thus, the suppressant effects of piperlactam S on proliferation of T cells activated by PHA seemed to be mediated, at least in part, through inhibition of early transcripts of T cells, especially those of important cytokines, IL-2, IL-4, and arresting cell cycle progression in the cells.

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The incidence of thyroid cancer increases with age, and it is twice in women as common as in men. The undifferentiated thyroid cancer (UTC) is the most aggressive of all thyroid cancers. Unfortunately, there are almost no efficacious therapeutic modalities. It is important to develop some new effective therapies. Evodiamine is a chemical extracted from a kind of Chinese herb named Wu-Chu-Yu and has been demonstrated to be effective in preventing the growth of a variety of cancer cells. In the present study, the mechanism by which evodiamine inhibited the undifferentiated thyroid cancer cell line ARO was examined. Based on 3-(4,5-dimethylthiazol -2-yle)2,5-diphenyltetrazolium bromide (MTT) assay, cell proliferation rate was reduced dose-dependently by evodiamine, but not by rutaecarpine. According to the flow cytometric analysis, evodiamine treatment resulted in G2/M arrest and DNA fragmentation in ARO cells. The G2/M arrest was accompanied with an increase of the expression of cdc25C, cyclin B1, and cdc2-p161 protein, and it was also with a decrease of the expression of cdc2-p15. Furthermore, by using the TUNEL assay, evodiamine-induced apoptosis was observed at 48 h and extended to 72 h. Western blotting demonstrated that evodiamine treatment induced the activation of caspase-8, caspase-9, caspase-3, and the cleavage of poly ADP-ribose polymerase (PARP). These results suggested that evodiamine inhibited the growth of the ARO cells, arrested them at M phase, and induced apoptosis through caspases signaling.