herbimycin and retinol-acetate

Cultured hepatic stellate cells were induced to elongate long, multipolar cellular processes by interstitial collagen gel used as a substratum, as compared to flattened or round cell shapes on polystyrene surface or on Matrigel containing the basement membrane components, respectively. The process induction was inhibited by several reagents as follows: (1) anti-integrin alpha2 antibody; (2) an oligopeptide, DGEA, an integrin-binding sequence in type I collagen molecule; (3) wortmannin, a phosphatidylinositol 3-kinase inhibitor. Protein tyrosine phosphorylation was enhanced throughout cells including cellular processes by culturing on type I collagen gel. Dual fluorescence staining showed that the core of the processes contained microtubules, whereas the periphery of the processes comprised fibrillar actin. Thus, the process extension was found to depend on integrin-binding to type I collagen fibres, followed by signal transduction and cytoskeleton assembly. The cellular processes included interstitial collagenase and vitamin A-containing lipid droplets. The lipid droplets and vitamin A-autofluorescence were increased by retinyl acetate addition to the culture medium, suggesting an important role of processes in hepatic stellate cell function.

Topics: Androstadienes; Animals; Antibodies, Monoclonal; Antigens, CD; Benzoquinones; Cells, Cultured; Collagen; Collagenases; Diterpenes; Drug Combinations; Enzyme Inhibitors; Gels; Humans; Integrin alpha2; Lactams, Macrocyclic; Laminin; Lipid Metabolism; Liver; Liver Neoplasms; Male; Matrix Metalloproteinase 1; Oligopeptides; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proteoglycans; Quinones; Rats; Rats, Wistar; Retinyl Esters; Rifabutin; Signal Transduction; Staurosporine; Tumor Cells, Cultured; Vitamin A; Wortmannin

Four retinoids, i.e. retinol (vitamin A), retinoic acid, retinyl acetate and synthetic chalcone carboxylic acid (Ch 55), were examined for their effects on embryonic angiogenesis using 4.5-day chorioallantoic membranes of chick embryo. The effects of these retinoids were compared with that of antibiotic herbimycin A, which was the most powerful inhibitor of the angiogenesis reported previously. The four retinoids strongly inhibited embryonic angiogenesis; the order of inhibitory activity was Ch 55 greater than retinoic acid greater than herbimycin A greater than retinyl acetate based on the dose required for the half-maximal inhibitory effect. The present results suggest that retinoids are effective inhibitors of angiogenesis, and can be applied for the management of certain diseases accompanied by aberrant angiogenesis, particularly that which occurs during progressive growth of solid tumors.

Topics: Animals; Benzoquinones; Chalcone; Chalcones; Chick Embryo; Diterpenes; Dose-Response Relationship, Drug; In Vitro Techniques; Lactams, Macrocyclic; Neovascularization, Pathologic; Quinones; Retinoids; Retinyl Esters; Rifabutin; Tretinoin; Vitamin A