Increase in E-selectin expression in umbilical vein endothelial cells by anticancer drugs and inhibition by cimetidine

Abstract

E-selectin is expressed on the surfaces of stimulated vascular endothelial cells and is sometimes involved in cancer cell metastasis. The H2-receptor antagonist cimetidine inhibits the increase in E-selectin expression on vascular endothelial cells that is induced by interleukin-1beta (IL-1beta) and cimetidine. It also inhibits the adhesion of sialyl-Lewis-antigen-positive cancer cells to vascular endothelial cells, ultimately inhibiting hematogenous metastasis. Anticancer drugs are essential to cancer therapy, but whether they can alter the expression of E-selectin in vascular endothelial cells remains unclear. Whether cimetidine inhibits the expression of E-selectin in the same manner in the presence or absence of anticancer drugs also remains unknown. Human umbilical vein endothelial cells were cultured with 5-fluorouracil (5-FU), doxorubicin (DXR), cisplatin (CDDP), or IL-1beta and with or without cimetidine. The expression of E-selectin at the mRNA and protein levels was then determined using quantitative reverse transcription-polymerase chain reaction and immunohistochemical staining, respectively. The E-selectin mRNA level increased in cells exposed to 5-FU, DXR, or CDDP, but the addition of cimetidine had no effect on the E-selectin mRNA level. The expression of E-selectin protein was also significantly higher after the addition of 5-FU, DXR, or CDDP, compared with that of a negative control. However, when cimetidine was added prior to the addition of 5-FU, DXR, or CDDP, the expression of E-selectin was significantly suppressed. Thus, cimetidine significantly inhibited the expression of E-selectin at the protein level without affecting its expression at the mRNA level in cells treated with anticancer drugs. In conclusion, anticancer drugs increased the expression of E-selectin and this increase was inhibited by cimetidine. These findings suggest that the administration of cimetidine during treatment with anticancer drugs might be useful for preventing metastasis.