Tanshinone ⅡA Enhances The Chemosensi-Tivity Of Doxorubicin In Breast Cancer Cells By Inhibiting β-catenin Nuclear Translocation

ObjectiveTo explore that whether tanshinone ⅡA(Tan Ⅱ A)can enhance the chemosensitivity of doxorubicin(Dox)in breast cancer cells by inhibitingβ-catenin nuclear translocation.Methods1.Human breast cancer MCF-7 and MCF-7/dox cells were treated with different concentrations of Tan ⅡA(0.01,0.02,0.04,0.06,0.08,0.1,0.5,1mg/L)for 24 hours,MTS assay was used to detect cell proliferation,then we chosed the nontoxic dose(critical concentration)which has no effect on cell proliferation.2.Human breast cancer MCF-7 and MCF-7/dox cells were respectively treated with Tan Ⅱ A,Dox,Dox plus Tan Ⅱ A,or Dox plus Tan ⅡA plus β-catenin agonist WAY-262611,and set up the control group without drugs,after 24 hours,the following related tests were conducted:(1)MTS assay was used to detect the cell proliferation in each group.(2)Scratch assay was used to detect the cell migration in each group.(3)Western-blot assay was used to detect the expression of proteins such as β-catenin,c-Myc,E-cadherin,MMP2 and MMP9 in human breast cancer MCF-7 and MCF-7/dox cells.Results1.Compared with Dox-sensitive MCF-7 cells,the expressions of total and nuclear β-catenin and the ratio of β-catenin between nuclear and cytoplasm in Dox-resistant MCF-7/dox cells were significantly increased(P<0.05).2.Compared with Dox alone,the expressions of total and nuclear β-catenin and the ratio of β-catenin between nuclear and cytoplasm in MCF-7 and MCF-7/dox cells treated by Dox combined with Tan ⅡA were significantly decreased(P<0.05),and the Dox-resistant MCF-7/dox cells were more apparent.Meanwlile,the expressions of c-Myc,MMP2 and MMP9 in MCF-7 and MCF-7/dox cells treated by Dox combined with Tan ⅡA were significantly decreased(P<0.05),while the expression of E-cadherin was significantly increased(P<0.05).3.Tan ⅡA can significantly enhance the inhibitory effect of Dox on MCF-7 and MCF-7/dox cells proliferation(P<0.05),but after β-catenin agonist WAY-262611 intervention,the enhanced effect of Tan ⅡA on Dox inhibition of MCF-7 and MCF-7/dox cells proliferation was significantly reduced(P<0.05).4.TanⅡA can significantly enhance the inhibitory effect of Dox on MCF-7 and MCF-7/dox cells migration(P<0.05),but after β-catenin agonist WAY-262611 intervention,the enhanced effect of Tan ⅡA on Dox inhibition of MCF-7 and MCF-7/dox cells migration was significantly reduced(P<0.05).5.After β-catenin agonist WAY-262611 intervention,the expressions of total and nuclear β-catenin and the ratio of β-catenin between nuclear and cytoplasm in MCF-7 and MCF-7/dox cells treated by Dox combined with Tan ⅡA were significantly increased(P<0.05),and the expressions of c-Myc,MMP2 and MMP9 of its downstream were significantly increased(P<0.05),while the expression of E-cadherin was significantly decreased(P<0.05).ConclusionsTan ⅡA enhances the chemosensitivity of doxorubicin in breast cancer cells by inhibiting β-catenin nuclear translocation,thus Tan ⅡA can be used as a potential chemosensitizer in combination with Dox for the treatment of breast cancer.