title: Induction of G1 arrest and selective growth inhibition by lactacystin in human umbilical vein endothelial cells.
abstract: In search for angiogenesis inhibitors, we tested protease and proteasome inhibitors for the induction of G1 arrest and selective inhibition of growth of human umbilical vein endothelial cells (HUVECs). Serine protease-, cysteine protease-, aspartate protease-, and aminopeptidase-inhibitors did not inhibit bFGF/FBS-induced S-phase induction in HUVECs, but a proteasome inhibitor, lactacystin did inhibit it reversibly. Lactacystin increased the cellular level of p53 and cdk2-associated p21WAF1/CIP1 leading to cdk2 inactivation. In addition to the angiogenesis inhibitor TNP-470, lactacystin also inhibited the growth of HUVECs selectively at about a 20 times lower concentration than that of other human cell lines, including normal fibroblasts and carcinoma cells. Lactacystin induced p53-dependent p21WAF1/CIP1 expression at lower concentrations in HUVECs than in other cells. These cellular effects were also observed with a tripeptide-type proteasome inhibitor, N-Ac-Leu-Leu-norleucinal.
authors.affiliation: Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama, Japan.
authors.forename: S I
authors.initials: SI
authors.lastname: Kumeda
authors.forename: A
authors.initials: A
authors.lastname: Deguchi
authors.forename: M
authors.initials: M
authors.lastname: Toi
authors.forename: S
authors.initials: S
authors.lastname: Omura
authors.forename: K
authors.initials: K
authors.lastname: Umezawa
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism; D042846:CDC2-CDC28 Kinases; D002455:Cell Division / Q000187:drug effects*; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects*; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014471:Umbilical Veins / Q000187:drug effects*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D016159:Tumor Suppressor Protein p53; C063261:acetylleucyl-leucyl-norleucinal; C067713:lactacystin; D005346:Fibroblast Growth Factors; D003513:Cycloheximide; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D000111:Acetylcysteine