Curcumin (Cur), a component of turmeric (Curcuma longa), has been reported to exhibit antimetastatic activities, but the mechanisms remain unclear. Other
curcuminoids present in turmeric,
demethoxycurcumin (DMC) and
bisdemethoxycurcumin (BDMC) have not been investigated whether they exhibit antimetastatic activity to the same extent as
curcumin. The regulation of
matrix metalloproteinases (
MMPs) and
urokinase plasminogen activator (uPA) play important role in
cancer cell invasion by cleavage of extracellular matrix (ECM). In this line, we comparatively examined the influence of Cur, DMC and BDMC on the expressions of uPA, MMP-2, MMP-9, membrane Type 1
MMP (MT1-MMP),
tissue inhibitor of metalloproteinases (TIMP-2), and in vitro invasiveness of human
fibrosarcoma cells. The results indicate that the differential potency for inhibition of
cancer cell invasion was BDMC> or =DMC>Cur, whereas the cell migration was not affected. Zymography analysis exhibited that
curcumin, DMC and BDMC significantly decreased uPA, active-MMP-2 and MMP-9 but not
pro-MMP-2 secretion from the cells in a dose-dependent manner, in which BDMC and DMC show higher potency than
curcumin. The suppression of active MMP-2 level correlated with inhibition of
MT1-MMP and
TIMP-2 protein levels involved in
pro-MMP-2 activation. Importantly, BDMC and DMC
at 10 microM reduced
MT1-MMP and
TIMP-2 protein expression, but
curcumin slightly reduced only
MT1-MMP but not
TIMP-2. In addition, three forms of
curcuminoids significantly inhibited
collagenase, MMP-2, and MMP-9 but not uPA activity. In summary, these data demonstrated that DMC and BDMC show higher antimetastasis potency than
curcumin by the differentially down-regulation of ECM degradation
enzymes.