Cimetidine inhibits cancer cell adhesion to endothelial cells and preventsmetastasis by blocking E-selectin expression

Although the beneficial effect of cimetidine on survival in cancer has been clinically demonstrated in colorectal cancer patients, the mode of action of cimetidine has not been elucidated. In this report, we have demonstrated for the first time that cimetidine can block the adhesion of a colorectal tumor cell line to the endothelial cell monolayer in cell culture and that it can suppress the metastasis of the tumor cell in a nude mouse model. We also demonstrated that these antimetastasis effects of cimetidine might occ ur through down-regulation of the cell surface expression of E-selectin on endothelial cells, a ligand for sialyl Lewis antigens on tumor cells. We fo und that the cimetidine-mediated down-regulation of E-selectin did not invo lve down-regulation of E-selectin mRNA or blocking of the nuclear transloca tion of nuclear factor kappa B, a transcriptional activator of E-selectin g ene expression. Because two other histamine type 2 receptor antagonists, fa motidine and ranitidine, did not show any similar effect, these actions of cimetidine probably do not occur via blocking of the histamine receptor. Th ese observations support the idea that cancer metastasis can be blocked by cimetidine administration through blocking the adhesion of tumor cells to t he endothelium when an interaction between E-selectin and sialyl-Lewis anti gens plays a role.