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pubmed:abstractText |
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.
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