G. Melillo et al., Flavopiridol, a protein kinase inhibitor, down-regulates hypoxic inductionof vascular endothelial growth factor expression in human monocytes, CANCER RES, 59(21), 1999, pp. 5433-5437
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.