We found that
oral administration of the
benzoic acid derivative,
TAC-101 ¿4-[3,5-bis(trimethylsilyl)benzamido] benzoic acid¿ significantly inhibited experimental liver
metastasis of murine colon 26-L5
carcinoma cells, whereas
all-trans-retinoic acid (ATRA) did not show any inhibitory effect. Treatment with more than 10 microM
TAC-101 for 24 h showed direct cytotoxicity against
tumor cells in vitro. In contrast, ATRA did not have any direct cytotoxicity.
TAC-101 also inhibited the
tumor cell invasion enhanced by TPA (12-O-tetradecanoylphorbol-13-
acetate; AP-1 activator) in a concentration-dependent manner, whereas ATRA did not. Furthermore, zymographic analysis revealed that noncytotoxic concentrations (< 10 microM) of
TAC-101 inhibited TPA-induced production of
urokinase-type plasminogen activator (
u-PA) and
matrix metalloproteinase (MMP)-9 from
tumor cells, which is considered to be associated with their invasive and metastatic potentials. These results suggest that such an inhibitory effect is partly due to the ability of
TAC-101 to bind a
retinoic acid receptor (RAR)-alpha and consequently inhibit
metastasis-related gene transcription by interfering with AP-1/
DNA binding, as we showed previously. On the other hand,
TAC-101 also inhibited the production of MMP-2, which is not affected by TPA. Therefore, the antimetastatic effect of
TAC-101 includes an alternative regulatory mechanism for
MMP production. These results indicate that the in vivo antimetastatic effect of
TAC-101 is partly due to the cytotoxicity against
tumor cells, which may be caused by the induction of apoptosis, and inhibition of the production of invasion-associated
proteolytic enzymes.