Curcuminoids inhibit the angiogenic response stimulated by fibroblast growth factor-2, including expression of matrix metalloproteinase gelatinase B

We have studied mechanisms controlling activation of the gelatinase B gene (matrix metalloproteinase-g) by fibroblast growth factor-a (FGF-2) during angiogenesis, and the effects of the natural product curcuminoids on this process. Using a transgenic mouse (line 3445) harboring a gelatinase B promoter/lacZ fusion gene, we demonstrate FC;F-S stimulation of reporter gene expression in endothelial cells of invading neocapillaries in the corneal micropocket assay. Using cultured corneal cells, we show that FGF-S stimulates DNA binding activity of transcription factor AP-1 but not NF-kappa B and that AP-1 stimulation is inhibited by curcuminoids, We further show that induction of gelatinase B transcriptional promoter activity in response to FGF-S is dependent on AP-1 but not NF-kappa B response elements and that promoter activity is also inhibited by curcuminoids. In rabbit corneas, the angiogenic response induced by implantation of an FGF-P pellet is inhibited by the coimplantation of a curcuminoid pellet, and this correlates with inhibition of endogenous gelatinase B expression induced by FGF-2. Angiostatic efficacy in the cornea is also observed when curcuminoids are provided to mice in the diet. Our findings provide evidence that curcuminoids target the FGF-2 ansogenic signaling pathway and inhibit expression of gelatinase B in the angiogenic process.