Synergistic Inhibition of Breast Cancer Cell Growth by an Epigenome-Targeting Drug and a Tyrosine Kinase Inhibitor

Abstract

Background: Epigenome-targeting drugs, for example, histone decetylases (HDACs) inhibitors, have been recently shown to induce apoptosis in a variety of cancer cells, which could potentially be used as anticancer therapy. Tyrosine kinase inhibitors (TKIs) have been widely used in clinical trials of various cancers. HDAC inhibitor vorinostat, TKIs dasatinib have been tested in pivotal phase 2 clinical trials in patients with breast cancer. The combination treatment of vorinostat with dasatinib is expected to have synergistic effect on inhibiting breast cancer cell growth. Materials and Methods: Antiproliferation effects of the combined drugs on MCF-7 cells were designed according to Chou–Talalay method and analyzed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell-cycle perturbation and cell apoptosis induction of the combination drugs were examined by Flow cytometry. The generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential, and the expression of Bcl-2 were determined by Western blot. Results: Our results revealed that the combination treatment had synergistic effects on anti-MCF7 cells, enhanced G₂/M cell arrest, the generation of ROS, the loss of mitochondrial membrane potential, and cell apoptosis in MCF-7 cells in synergy. Moreover, the combination treatment decreased Bcl-2 expression. Conclusion: Our results demonstrated that the combination of vorinostat with dasatinib exerted synergistic anticancer effects on MCF-7 cells by inducing cell cycle arrest, ROS production, and apoptosis through the mitochondria-mediated intrinsic pathway.

Graphical Abstract