Medicinal plants contain pharmacological substances including
flavonoids, and their extracts have been therapeutically administered for
cancer therapy in vitro and in vivo. We investigated the efficacy of a polymethoxy
flavonoid,
nobiletin, from Citrus depressa on
tumor invasion in vitro.
Nobiletin inhibited the
tumor-invasive activity of human
fibrosarcoma HT-1080 cells in the
Matrigel model, whereas a similar inhibition was observed upon exogenously adding tissue inhibitors of
metalloproteinases (TIMPs)-1 and -2. The gene expression and production of
pro-matrix metalloproteinase 9 (proMMP-9)/
progelatinase B and proMMP-1/interstitial
procollagenase were specifically suppressed by
nobiletin in 12-O-tetradecanoylphorbol 13-acetate-stimulated HT-1080 cells. In contrast, the gene expression and production of
TIMP-1, but not
TIMP-2, were enhanced by
nobiletin. We also demonstrated that
nobiletin suppressed the 12-O-tetradecanoylphorbol 13-acetate-induced binding activity of
activator protein-1. Furthermore, a
phosphatidylinositol 3-kinase inhibitor,
LY-294002, was found to mimic the different actions of
nobiletin on the production of
proMMP-9 and
TIMP-1. These results suggest that
nobiletin inhibits
tumor cell invasive activity not only by suppressing the expression of
MMPs but also augmenting
TIMP-1 production in
tumor cells, and that the
nobiletin-mediated inhibition of
activator protein-1 binding activity is at least partly involved in the suppression of
MMP expression. Furthermore, we suggest a possible mechanism by which
nobiletin may interfere in the
phosphatidylinositol 3-kinase pathway, which divergently regulates the production of
MMP and
TIMP-1.