sc-236 and Cell-Transformation--Neoplastic

Fractionation of an ethyl acetate-soluble extract of the bark of Artocarpus dadah has led to the isolation of three new prenylated stilbenoid derivatives, 3-(gamma,gamma-dimethylallyl)resveratrol (1), 5-(gamma,gamma-dimethylallyl)oxyresveratrol (2), 3-(2,3-dihydroxy-3-methylbutyl)resveratrol (3), and a new benzofuran derivative, 3-(gamma,gamma-dimethylpropenyl)moracin M (4), along with six known compounds, oxyresveratrol, (+)-catechin, afzelechin-3-O-alpha-L-rhamnopyranoside, (-)-epiafzelechin, dihydromorin, and epiafzelechin-(4beta-->8)-epicatechin. From an ethyl acetate-soluble extract of the twigs of the same plant were isolated compound 4 and two new neolignan derivatives, dadahols A (5) and B (6), as well as 10 known compounds, oxyresveratrol, (+)-catechin, afzelechin-3-O-alpha-L-rhamnopyranoside, resveratrol, steppogenin, moracin M, isogemichalcone B, gemichalcone B, norartocarpetin, and engeletin. The structures of compounds 1-6 were determined using spectroscopic and chemical methods. Isolates were evaluated for their inhibitory effects against both cyclooxygenase-1 (COX-1) and -2 (COX-2) and in a mouse mammary organ culture assay.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Acetylation; Animals; Benzofurans; Breast; Catechin; Cell Transformation, Neoplastic; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; Indonesia; Isoenzymes; Membrane Proteins; Methylation; Mice; Mice, Inbred BALB C; Molecular Structure; Moraceae; Nuclear Magnetic Resonance, Biomolecular; Organ Culture Techniques; Plant Bark; Plant Extracts; Plant Shoots; Plants, Medicinal; Prostaglandin-Endoperoxide Synthases; Spectroscopy, Fourier Transform Infrared; Stereoisomerism; Stilbenes

In human colorectal adenomas or polyps, cyclooxygenase-2 is expressed predominantly by stromal (or interstitial) macrophages. Therefore, we tested the hypothesis that macrophage cyclooxygenase-2 has paracrine pro-tumorigenic activity using in vitro models of macrophage-epithelial cell interactions. We report that macrophages can promote tumorigenic progression of intestinal epithelial cells (evidenced by decreased cell-cell contact inhibition, increased proliferation and apoptosis, gain of anchorage-independent growth capability, decreased membranous E-cadherin expression, up-regulation of cyclooxygenase-2 expression, down-regulation of transforming growth factor-beta type II receptor expression and resistance to the anti-proliferative activity of transforming growth factor-beta(1)) in a paracrine, cyclooxygenase-2-dependent manner. Pharmacologically relevant concentrations (1-2 microM) of a selective cyclooxygenase-2 inhibitor had no detectable, direct effect on intestinal epithelial cells but inhibited the macrophage-epithelial cell signal mediating tumorigenic progression. Cyclooxygenase-2-mediated stromal-epithelial cell signalling during the early stages of intestinal tumorigenesis provides a novel target for chemoprevention of colorectal cancer (and other gastro-intestinal epithelial malignancies, which arise on a background of chronic inflammation, such as gastric cancer) and may explain the discrepancy between the concentrations of cyclooxygenase inhibitors required to produce anti-neoplastic effects in vitro and in vivo.

Topics: Animals; Cell Transformation, Neoplastic; Cells, Cultured; Cyclooxygenase 2; Dinoprostone; Epithelial Cells; Intestines; Isoenzymes; Macrophage Activation; Macrophages; Mice; Paracrine Communication; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Sulfonamides