LAUSR

ABSTRACT Chalcone (1,3‐diphenyl‐2‐propen‐1‐one) derivatives exert anti‐cancer activity by targeting key molecules that can lead to carcinogenesis. We synthesized the chalcone derivative 3‐phenyl‐1‐(2,4,6‐tris(methoxymethoxy)phenyl)prop‐2‐yn‐1‐one (KB‐34) and previously reported its anti‐inflammatory activity in macrophages. In this study, we examined the anti‐metastatic activity of KB‐34 against human colorectal cancer (CRC) cells and elucidated its underlying molecular mechanisms. KB‐34 treatment significantly inhibited 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA)‐induced migration, as well as the invasion and proliferation of CRC cells (HT‐29 and SW620). TPA‐induced activation of NF‐&kgr;B was also markedly suppressed by KB‐34 in HT‐29 cells. KB‐34 suppressed the expression of matrix metalloproteinase‐7 (MMP‐7) at both the mRNA and protein levels in TPA‐stimulated CRC cells (HT‐29 and SW620). We also demonstrated that induced heme oxygenase‐1 (HO‐1) expression in CRC cells (HT‐29 and SW620) and HO‐1 is required for KB‐34‐mediated suppression of the expression of MMP‐7 in TPA‐stimulated HT‐29 cells. Additionally, the cyclin‐dependent kinase inhibitor p21 was significantly induced by treatment with KB‐34 in CRC cells (HT‐29 and SW620). Knockdown of HO‐1 prevented the induction of p21 expression by KB‐34 in HT‐29 cells. Furthermore, we also demonstrated that 5‐fluorouracil (5‐FU) together with KB‐34 produced a significantly greater inhibition of growth and stimulation of apoptosis of HT‐29 cells than did 5‐FU alone. In conclusion, KB‐34 inhibits the TPA‐stimulated metastatic potential of HT‐29 cells by induction of HO‐1 and may be a promising anti‐cancer agent in chemotherapeutic strategies for CRC.