R. Mohan et al., Curcuminoids inhibit the angiogenic response stimulated by fibroblast growth factor-2, including expression of matrix metalloproteinase gelatinase B, J BIOL CHEM, 275(14), 2000, pp. 10405-10412
We have studied mechanisms controlling activation of the gelatinase B gene
(matrix metalloproteinase-g) by fibroblast growth factor-a (FGF-2) during a
ngiogenesis, and the effects of the natural product curcuminoids on this pr
ocess. Using a transgenic mouse (line 3445) harboring a gelatinase B promot
er/lacZ fusion gene, we demonstrate FC;F-S stimulation of reporter gene exp
ression in endothelial cells of invading neocapillaries in the corneal micr
opocket 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 th
at AP-1 stimulation is inhibited by curcuminoids, We further show that indu
ction 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 promot
er activity is also inhibited by curcuminoids. In rabbit corneas, the angio
genic response induced by implantation of an FGF-P pellet is inhibited by t
he coimplantation of a curcuminoid pellet, and this correlates with inhibit
ion of endogenous gelatinase B expression induced by FGF-2. Angiostatic eff
icacy in the cornea is also observed when curcuminoids are provided to mice
in the diet. Our findings provide evidence that curcuminoids target the FG
F-2 ansogenic signaling pathway and inhibit expression of gelatinase B in t
he angiogenic process.