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Wild lowbush blueberry fruit extract was fractionated using vacuum chromatography and analyzed for chemopreventive potential using bioassays that test the ability of compounds to inhibit the initiation, promotion, and progression stages of carcinogenesis. A fraction containing phytosterols was active against the initiation stage (quinone reductase assay). However, more polar compounds were inhibitors of later stages of carcinogenesis; a fraction containing flavan-3-ols and fractions containing mainly anthocyanins, phenolic acids, flavan-3-ols, and some proanthocyanidin dimers demonstrated activity against the promotion stage (cyclooxygenase and ornithine decarboxylase assays, respectively), and a proanthocyanidin-rich fraction demonstrated antiproliferation activity (inhibition of cancerous murine hepatocyte proliferation is associated with the progression stage). These results indicate that lowbush blueberries contain a range of compounds that have bioactivity against multiple stages of carcinogenesis, and different types of phenolic compounds are active at different stages.

α-Tocopheryl succinate (TOS), a vitamin E analog, is a promising anticancer agent due to its abilities to inhibit proliferation and to induce apoptosis in a variety of human malignant cell lines, while being relatively less active toward normal cells. However, the molecular mechanisms underlying the apoptotic effects of TOS are not precisely understood. Reports that TOS can generate reactive oxygen species (ROS) prompted us to investigate the role of ROS in TOS-induced apoptosis in cancer cells. We found that the human lung cancer A549 and H460 cell lines were much more sensitive to TOS-induced apoptosis than the human glioblastoma T98G and U87MG cell lines. Our data suggested that the differential TOS sensitivity was not caused by differences in the uptake and retention of TOS between TOS-sensitive and –resistant cancer cells. The differential ability of cancer cells to generate ROS in response to TOS appears to be an important factor in determining the susceptibility of cells to TOS-induced apoptosis. Our results further suggest that TOS-induced generation of ROS is involved in caspase-independent apoptosis. Taken together, our findings suggest an important role of ROS generation in TOS-induced, caspase-independent apoptosis of cancer cells. © 2004 Wiley-Liss, Inc.

β-Catenin serves not only as a structural component of the E-cadherin-mediated cell–cell adhesion system, but also as a signaling molecule of the Wnt/wingless pathway. Deregulated expression of β-catenin and mutations of the gene have been identified in a number of human malignancies. To determine the role of β-catenin defects in stomach cancer, we investigated β-catenin exon 3 mutations and altered protein expression in 77 primary gastric carcinomas and 11 cell lines. In addition, the immunohistochemical expression pattern of β-catenin in 303 consecutive gastric cancers was determined and their relationships with clinicopathologic features and patient outcome were investigated. This study revealed 5% (4 of 77) tumors and 27% (3 of 11) cell lines with β-catenin gene alteration, 6 missense mutations, and 1 interstitial deletion. These genetic changes were shown to correlate closely with nuclear localization of the protein (p = 0.001). In an immunohistochemical analysis, abnormal expressions of β-catenin, such as nuclear accumulation and loss of membranous distribution, were detected in 27% (81 of 303) of tumors overall. These altered β-catenin expressions were more commonly observed in 37% (58 of 158) diffuse type gastric carcinomas (p < 0.001). Loss of membranous β-catenin staining was associated with poor survival (p = 0.045). In conclusion, our results demonstrate that β-catenin mutations are common in gastric cancer cell lines but occur infrequently in gastric carcinoma tissues. These mutations are one of the causes of the nuclear accumulation of β-catenin. Frequent abnormalities of β-catenin expression in gastric carcinoma support the idea that both structural and signaling functions of the protein play a critical role in gastric carcinogenesis. © 2001 Wiley-Liss, Inc.

An antimetastatic and cytostatic substance, termed AC7-1, was isolated from Ardisia crispa and identified as a benzoquinonoid compound, 2-methoxy-6-tridecyl-1,4-benzoquinone. It was originally characterized as the potent PAF (platelet-activating factor) receptor-binding antagonist with nonspecific antiplatelet effects on platelet aggregation induced by various agonists including PAF, ADP, thrombin and collagen. The nonspecific antiaggregatory properties of AC7-1 drew our interest given its possible relationship in integrin receptor-binding antagonistic activity. The integrin receptor plays an important role in metastasis and thrombosis as the cell surface transmembrane protein. Based on the aforementioned facts, the antimetastatic activities of AC7-1 were examined using various in vitro and in vivo metastasis assays. AC7-1 strongly blocked B16-F10 melanoma cell adhesion to extracellular matrix (ECM) and B16-F10 melanoma cell invasion. AC7-1 also remarkably inhibited pulmonary metastasis and tumor growth in vivo. AC7-1 inhibited B16-F10 melanoma cell adhesion to only specific synthetic peptides including RGDS. These findings suggest that antimetastatic activities of AC7-1 can be caused by blocking integrin-mediated adherence. We found AC7-1 to be a potential candidate for the development of a new antimetastatic drug.

The bioassay-guided purification of ether extracts of Alpinia officinarum led to the isolation of two new compounds 6-hydroxy-1,7-diphenyl-4-en-3-heptanone ( 1 ) and 6-(2-hydroxy-phenyl)-4-methoxy-2-pyrone ( 4 ) as well as three known compounds 1,7-diphenyl-4-en-3-heptanone ( 2 ), 1,7-diphenyl-5-methoxy-3-heptanone ( 3 ), and apigenin ( 5 ). Their structures were established on the basis of spectral methods. All three diarylheptanoids 1 , 2 , and 3 exhibited potent PAF receptor binding inhibitory activities with an IC 50 of 1.3, 5.0, and 1.6 μM, respectively. These studies have identified diarylheptanoids as a novel class of potent PAF antagonists.

A C29-triterpene, beccaridiol (1), a dihydrochalcone natural product, 2',4'-dihydroxy-3-(4-methoxyphenyl)-propiophenone (2), as well as three known compounds, 4'-hydroxy-1',2'-dihydro-beta-ionone, 4'-O-methyldavidigenin (3), and ursolic acid, have been isolated from an EtOAc-soluble extract of the leaves of Diplectria beccariana. Beccaridiol (1) was characterized as an ursane-type 28-nortriterpene possessing an unusual aromatic E-ring by spectroscopic data interpretation. The relative configuration of this unusual isolate was established by analyzing the observed NOESY NMR correlations, and the absolute stereochemistry of 1 was then determined based on the circular dichroism (CD) spectrum of its 2,3-di-p-bromobenzoate (1b) derivative. All isolates were evaluated for their potential cancer chemopreventive properties utilizing a cell culture assay to determine quinone reductase induction.