Combination effect of a TGF-β receptor kinase inhibitor with 5-FU analog S1 on lymph node metastasis of scirrhous gastric cancer in mice

Transforming growth factor-beta (TGF-beta) signals are closely associated with the distant metastases of gastric cancer. The aim of this study was to clarify the effect of a TGF-beta receptor I (T beta R-I) phosphorylation inhibitor, Ki26894, in combination with anticancer drugs, on the lymph node (LN) metastasis of scirrhous gastric cancer. A novel T beta R-I kinase inhibitor, Ki26894, inhibits the phosphorylation of Smad2 at the ATP binding site of T beta R-I. S1 is a 5-fluorouracil analog. The human scirrhous gastric cancer cell line OCUM-2MLN and the human gastric fibroblasts NF-33 were used. OCUM-2MLM cells in the upper well and NF-33 cells in the lower well were co-incubated with or without Ki26894. The proliferation of OCUM-2MLN cells was significantly stimulated by co-culture with NF-33 cells. Ki26894 significantly suppressed the growth interactions between OCUM-2MLN cells and NF-33 cells. Gastric cancer models established by orthotopic inoculation of OCUM-2MLN cells showed diffusely infiltrating gastric adenocarcinoma accompanied by LN metastases. We divided these mice into four groups, (control vehicle, Ki26894, S1, Ki26894 plus S1), and examined the effect of Ki26894 and/or S1 on phosphorylation of Smad2, tumor size, LN metastases, and lymphatic involvements. Ki26894 inhibited the Smad2 phosphorylation of cancer cells and decreased the extent of lymphatic involvement, compared with the control or S1 only group. The Ki26894 plus S1 administration group significantly suppressed tumor growth and decreased LN metastasis more effectively than either alone. These findings suggested that the T beta R-I kinase inhibitor with S1 is useful for the treatment of scirrhous gastric carcinoma with LN metastasis. (Cancer Sci 2010).