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

K. Kobayashi, MD. PhD. a S. Matsumoto, MD. PhD. b T. Okamoto, MD. PhD. c

aDepartment of Surgery, b2nd Teaching Hospital, Fujita Health University, Medical School, Nagoya, aichi, Japan.cDepartment of Molecular Genetics, Nagoya City University, Medical School, Nagoya, aichi, Japan.

AIM: 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. Thus, in this study, we have attempted to examine the action of cimetidine by investigating its effect on the cancer cell adhesion to endothelial cells, one of the critical steps of cancer invasion and metastasis. METHODS AND RESULTS: We demonstrate for the first time that cimetidine can block the adhesion of a colorectal tumor cell line to the endothelial cell monolayer in cell cultures and that it can suppress the metastasis of tumor cells in a nude mouse model. We also found that these anti-metastasis effects of cimetidine might occur through down-regulation of the cell surface expression of E-selctin on endothelial cells, a ligand for sialyl Lewis antigens on tumor cells. Because two other histamine type 2 receptor antagonists, famotidine and ranitidine, did not show any similar effect, these actions of cimetidine may not occur via blocking of the histamine receptor. CONCLUSIONS: Cancer metastasis can be blocked by cimetidine administration through blocking the adhesion of tumor cells to the endothelium when an interaction between E-selectin and sialyl-Lewis antigens plays a role.

KEY WORDS: Histamine type 2 receptor antagonists, metastasis, cell adhesion, adhesion molecule, sialyl-Lewis antigen.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Metastasis.