Anti-adhesion Effect Of Interfers Cancer Cells To Vascular Endothelial Cells And The Underlying Mechanism Of S-nitroso Captopril

Objective:Today's society,the deaths resulting from cancer metastasis was greater than the primary tumor.Tumor metastasis was considered to be closely related to the circulating tumor cells(CTCs)in the blood.S-nitrosocaptopril(CAP-NO)possessed both the properties of nitric oxide and angiotensin coverting enzyme inhibitor(ACEI)and we first finished its physicochemical property,pharmacodynamics and toxicology study.It can inhibit platelet aggregation and exhibits the relax vascular.We supposed that CAP-NO had the potential to inhibit hetero-adhesion of tumor cells to human umbilical vein endothelial cells(HUVECs).We aimed at exploring the mechanism of CAP-NO on cellular hetero-adhesion between tumor cells and HUVECs at the molecular,cellular and animal level.Method:The inhibition effects of CAP-NO on the growth of cells were evaluated by MTT assay.Cell cycle distribution and mitochondrial membrance potential(??m)were measured by the flow cytometry.Fluorescence-based analysis was used to evaluate effects of CAP-NO on the hetero-adhesion between colon cancer cell HT-29 and HUVECs.The anti-adhesion result was evaluated by counting HT-29 cells that adhered to HUVECs.After HUVECs were pretreated by IL-1?,expression of HUVECs cell-surface VCAM-1,E-selectin and ICAM-1 was measured by flow cytometry and Western blot.The inhibition effects of CAP-NO on the aggregation of platelet and HT-29 cells.Moreover,mouse lung metastasis model was used to evaluate the anti-metastasis effects of CAP-NO.Results:The adhesion assay in vitro showed that CAP-NO could be hindered the adhesion of cellers and HUVECs in a dose-depended manner.Flow cytometry analysis showed that IL-1?,TNF-? and TNF-a significantly stimulated production by the highly-purified HUVECs of the CAMs.Flow cytometry showed that CAP-NO inhibited expression by the HUVECs of VCAM-1,ICAM-1,E-selectin in a dose-depended manner.The result from Western blot was consistent with the result from the flow cytometry analysis.CAP-NO had weak cytotoxicity on HUVECs,HT-29 and B16F10 cells at concentrations up to 1000 ?M.??m significant increase in HT-29 was observed only when concentration was up to 1000 ?M.CAP-NO did not have a significant effect on cell cycle distribution and ??m at the concentration of 100 ?M,which demonstrated that the inhibition of adhesion between HT-29 and HUVECs of CAP-NO was not due to its cytotoxicity.Flow cytometry analysis demonstrate that CAP-NO inhibited the aggregation of platelet and HT-29 cells.The date of anti-tumor in vivo showed that CAP-NO inhibit B16F10 cells transfer to mouse lungs in a dose-depended manner,decreasing the number of lung nudles in the metastatic model.Conclusion:The present study revealed that CAP-NO had weak cytoxicity against cells.These results showed that CAP-NO could interfered with the hetero-adhesion of cancer cells to HUVECs via inhibiting platelet activation and reducing the expression of CAMs.Moreover,the in vivo experiment demonstrated that CAP-NO could have inhibiting effect on tumor metastasis.Therefore,CAP-NO may have important significance for cancer metastasis.