We have established an in vitro angiogenesis model using human omental microvascular endothelial (HOME) cells, in which
epidermal growth factor (
EGF) or
transforming growth factor-alpha (
TGF-alpha) stimulated cell migration and tube formation. In this study, we examined whether
alpha-guaiaconic acid (GR-12) and its synthetic 20 derivatives showed inhibition of cell migration and tubular formation of HOME cells. We found that
GR-12 inhibits
arachidonic acid metabolism, while
GR-12 and one derivative,
GS-01, inhibit tubular formation of endothelial cells in our model system. Confluent monolayers of HOME cells were damaged with a razor blade and incubated with or without
TGF-alpha; HOME cell migration was stimulated about 1.5-fold over control values in the presence of
TGF-alpha. Treatment of HOME cells with
GR-12 or
GS-01 inhibited both spontaneous and
TGF-alpha-stimulated migration.
GR-12 or
GS-01 inhibited
TGF-alpha-induced HOME-cell tube formation in type-1
collagen gels. We examined whether these compounds could modulate tubular formation of HOME cells induced by human
cancer cells. Enhanced tube formation of HOME cells by co-cultured
esophageal cancer cells was almost completely inhibited by co-administration of
GR-12 or
GS-01. Both compounds also inhibited formation of tubular networks of HOME cells on Matrigels. We also examined anti-angiogenic activity of these compounds in an in vivo model system of
tumor angiogenesis in mice. In this system,
GS-01 inhibited development of capillary networks at a rate comparable to that of a well-known anti-angiogenic compound,
fumagillin, but
GR-12 did not. The inhibitor of
arachidonic acid metabolism is thus expected to modulate
tumor angiogenesis.