The Association Of 1a,25-dihydroxyvitamin D3 With Celecoxib Enhance The Effect Of Doxorubicin On Breast Cancer Cell Line MCF/ADR Via NF-κB Pathway

Objective To study the association of 1a,25-Dihydroxyvitamin D3 with celecoxib in ehancing the effect of doxorubicin on breast cancer cell line MCF/ADR and potential mechanism of NF-κB pathway.Methods MTT assay was used to detect the effect of 1a,25-Dihydroxyvitamin D3 and celecoxib on MCF-7/ADR cells proliferation and half inhibitory concentration (IC50) of doxorubicin. MCF/ADR cell apoptosis, intracellular concentration of doxorubicin and cell surface P-170 expression were determined by flow cytometry. The expression of NF-κB/p65 and IκBαwere examined by immunohistochemistry.Results1. The effect of 1a,25-Dihydroxyvitamin D3 associated with celecoxib on breast cancer cell line MCF/ADR 1, 25 dihydroxyvitamin D3 and celecoxib inhibited MCF / ADR cells proliferation in a time and concentration dependent respectively, and the two drugs used in combination showed synergy.2. The association of 1a,25-Dihydroxyvitamin D3 with celecoxib enhance the effect of doxorubicin on breast cancer cell line MCF/ADR①Administration of 1, 25 dihydroxyvitamin D3 50nmol/L and celecoxib 25umol/L reduced the IC50 of doxorubicin. 1, 25 dihydroxyvitamin D3, combined with celecoxib and the two drugs alone were significantly different.②A dministration of 1a,25-Dihydroxyvitamin D3 and celecoxib together inhibited MCF/ADR cells proliferation, induced cell apoptosis and increased cell sensitivity to doxorubicin.③1, 25 dihydroxyvitamin D3 and celecoxib reduced the expression of P170, increased intracellular concentration of doxorubicin. A combination of two drugs has been shown to be more effective than 1, 25 dihydroxyvitamin D3 or celecoxib alone.3. The relation between the effect of 1a,25-Dihydroxyvitamin D3 associated with celecoxib enhanced the activity of doxorubicin on breast cancer cell line MCF/ADR and NF-κB pathway Administration of doxorubicin increase the level of p65 and decrease the level of IκBα. In addition, combination of 1a,25-Dihydroxyvitamin D3 and celecoxib decreased p65 expression but increased IκBαexpression in MCF/ADR cells.Conclusion1. Administration of 1a,25-Dihydroxyvitamin D3 and celecoxib together inhibited M- CF/ADR cells proliferation, induced cell apoptosis. The combination of these two drugs resulted in a significantly decrease of surviving fraction compared with 1,25-D or celecoxib alone.2. The combination of 1, 25 dihydroxyvitamin D3 and celecoxib resulted in decrease IC50 of doxorubicin and the expresstion of P170, increase intracellular concentration of doxorubicin compared with single agent.3. 1a,25-Dihydroxyvitamin D3 associated with celecoxib enhanced doxorubicin sensitiveity of MCF/ADR cells probably through inhibiting NF-κB pathway thus promoting cell apoptosis.