Inhibitory effect of a selective cyclooxygenase-2 inhibitor on liver metastasis of colon cancer.

COX-2 overexpression is recognized in various cancers, but the role of COX-2 in the progression of cancer, including the liver metastasis of colon cancer, is not clearly understood. We examined the role of COX-2 in the mechanism of liver metastasis of colon cancer, using a highly metastasizable colon carcinoma cell line, LM-H3. A COX-2 inhibitor, JTE-522, inhibited cell proliferation and invasion of LM-H3 in vitro and clearly reduced the number of metastatic nodules on the surface of nude mouse livers in vivo. We also examined the effects of JTE-522 on the production of growth factors and MMPs through the use of ELISA and gelatin zymography, respectively. JTE-522 downregulated PDGF production by LM-H3 but had no influence on VEGF production. JTE-522 also inhibited MMP-2 secretion by LM-H3. JTE-522 downregulated PGE(2) production, but the associated changes in PGE(2) did not affect PDGF and VEGF production by LM-H3. We conclude that JTE-522 downregulated the cell proliferation and invasive potential of LM-H3 by reducing the production of PDGF and MMP-2 and hypothesize that these inhibitory effects on the production of PDGF and MMP-2 can lead to inhibition of liver metastasis of colon cancer. These data indicate that the COX-2 inhibitor JTE-522 has a high potential for use as a clinical agent for the treatment of liver metastasis of colon cancer. Copyright 2002 Wiley-Liss, Inc.