Flavopiridol, a protein kinase inhibitor, down-regulates hypoxic inductionof vascular endothelial growth factor expression in human monocytes

We have investigated the effects of flavopiridol, a novel protein kinase in hibitor that is selective for cyclin-dependent kinases, on hypoxia-induced vascular endothelial growth factor (VEGF) expression in human monocytes, We found that hypoxia induces a time-dependent increase of VEGF mRNA expressi on and protein levels in human monocytes, Flavopiridol showed a minimal eff ect on the constitutive levels of VEGF mRNA but completely blocked hypoxia- induced VEGF mRNA and protein expression. The inhibitory effects of flavopi ridol on VEGF mRNA induction also occurred in the presence of cycloheximide . The transcriptional activation of either a VEGF promoter-luciferase const ruct or a hypoxia-inducible factor 1 reporter plasmid was not affected by a ddition of flavopiridol in transient transfection experiments. In contrast, actinomycin D experiments demonstrated that flavopiridol dramatically decr eased VEGF mRNA stability. These data provide the first evidence that flavo piridol can affect gene expression by altering mRNA stability. We propose t hat flavopiridol may interfere with one or more signaling events, leading t o hypoxia-induced, protein kinase-modulated, RNA protein binding activity. An important clinical implication of our results is that flavopiridol, pres ently under investigation in clinical trials, might have antiangiogenic as well as direct antiproliferative effects.