UCN-01, a protein kinase C inhibitor, inhibits endothelial cell proliferation and angiogenic hypoxic response

Angiogenesis is required for tumor formation and growth; inhibition of angi ogenesis is a promising new approach in cancer therapy. UCN-01, a protein k inase C (PKC) inhibitor, induces growth arrest and apoptosis in cancer cell s and was recently introduced in a phase I clinical trial. We demonstrate t hat UCN-01, at concentrations lower than those necessary to inhibit cancer cell growth, inhibit proliferation of human endothelial cells in vitro. Mor eover, UCN-01, at concentrations as low as 32 nM prevent microvessel outgro wth from explant cultures of rat aortic rings. Since hypoxia activates hypo xia-inducible factor (HIF-1)-dependent transcription in cancer cells that, in a paracrine fashion, drive tumor angiogenesis, we investigated the effec ts of UCN-01 on HIF-1-responsive promoter constructs. We report that, in ad dition to direct inhibitory effects on endothelial cell growth, UCN-01 abro gates hypoxia-mediated transactivation of HIF-1-responsive promoters in a p rostate cancer cell line. We conclude that UCN-01, at clinically relevant c oncentrations, exerts an anti-neovascularization effect by blocking two imp ortant steps in vessel formation: (1) the response of cancer cells to hypox ia, and (2) endothelial cell proliferation. Copyright (C) 2000 S. Karger AG , Basel.