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 angiogenesis is a promising new approach in cancer therapy. UCN-01, a protein kinase C (PKC) inhibitor, induces growth arrest and apoptosis in cancer cells and was recently introduced in a phase I clinical trial. We demonstrate that UCN-01, at concentrations lower than those necessary to inhibit cancer cell growth, inhibit proliferation of human endothelial cells in vitro. Moreover, UCN-01, at concentrations as low as 32 nM, prevent microvessel outgrowth from explant cultures of rat aortic rings. Since hypoxia activates hypoxia-inducible factor (HIF-1)-dependent transcription in cancer cells that, in a paracrine fashion, drive tumor angiogenesis, we investigated the effects of UCN-01 on HIF-1-responsive promoter constructs. We report that, in addition to direct inhibitory effects on endothelial cell growth, UCN-01 abrogates hypoxia-mediated transactivation of HIF-1-responsive promoters in a prostate cancer cell line. We conclude that UCN-01, at clinically relevant concentrations, exerts an anti-neovascularization effect by blocking two important steps in vessel formation: (1) the response of cancer cells to hypoxia, and (2) endothelial cell proliferation.
Kruger
E A
EA
Medicine Branch, Division of Clinical Sciences, National Cancer Institute, NIH, Bethesda, MD., USA.
Blagosklonny
M V
MV
Dixon
S C
SC
Figg
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WD
D000470:Alkaloids / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D015687:Cell Hypoxia / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008297:Male; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009687:Nuclear Proteins / Q000502:physiology; D009924:Organ Culture Techniques; D011471:Prostatic Neoplasms / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019311:Staurosporine / Q000031:analogs & derivatives; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000470:Alkaloids; D020533:Angiogenesis Inhibitors; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C054852:7-hydroxystaurosporine; D011493:Protein Kinase C; D019311:Staurosporine