The Anticancer Activity And Mechanism Of Histone Deacetylase Inhibitor In Combination With Lapatinib In Breast Cancer Cells

Objective : To observe the inhibitory effect of Panobinostat in combination with Lapatinib on proliferation in breast cancer cells.Methods:The breast cancer cell line SK-BR3 was cultured in vitro and treated by different concentration of Panobinostat and(or) Lapatinib for 72 h. Proliferation of cells were detected by WST-1 methods, expression of mRNA and protein of ERBB1, ERBB2 or ERBB3, and phosphorylation of AKT, ERK1/2 or H2 A.X and PARP were measured by RT-PCR and Western blot, respectively. Apoptosis of cells was detected by flow cytometry.Results:As the concentration of Panobinostat and(or) Lapatinib increased, the inhibitory effect on SK-BR3 proliferation was also increased. Then the inhibitory rate reached to 50%, the combination index was 0.59,SK-BR3 cells were treated with 15nmol/L of Panobinostat, the expression of ERBB1 and ERBB2 mRNA significantly decreased. And the protein expression level of EGFR and Her2 decreased also,showed in dose-dependent manner. In addition, the expression of ERBB1 and ERBB2 mRNA and EGFR and Her2 protein was inhibited by treatment of 0.3μmol/L of Lapatinib, but it could significantly decrease the mRNA and protein level of EGFR and Her2 when in combination with Panobinostat. 0.3μmol/L of Lapatinib perse could affect the expression of the mRNA and protein of Her3. Although 15nmol/L of Panobinostat could also inhibit Her3 expression, but could further abrogate it when in combination with 0.3μmol/L Lapatinib. In addition, co-incubation of 0.3μmol/L Lapatinib and 15nmol/L Panobinostat could decrease the phosphorylation of AKT and ERK1/2. 15nmol/L Panobinostat did not show any effect on the apoptosis of SK-BR3, but 0.3μmol/L of Lapatinib could slightly inhibit it. When the Panobinostat was used in combination with Lapatinib, the apoptosis of cells were significantly induced and the phosphorylated γ-H2 A.X and the PARP level was increased.Conclusio:Lapatinib could synergistically enhance the antitumor activity of Panobinostat in breast cancer cells by induction of apoptosis,which may be caused by the inhibiton of AKT /ERK signal transduction pathway。.