The effect of combined treatment with capecitabine and mocetinostat (HDAC inhibitor) on apoptosis mechanism in breast cancer tumor model: In vivo and in vitro investigation

TNBC (triple negative breast cancer) is still of clinical importance due to its poor prognosis, aggressive nature and lack of targeted therapy. New data are needed to support new treatment strategies for the treatment of TNBC. One of the ways to treat cancer is to control the uncontrolled growth of cancer cells or to terminate cell growth. Apoptosis is one of the effective mechanisms in the prevention of cancer. Since apoptosis is not specific to the cause and type of cancer, it is a highly effective way to treat all cancers, including breast cancer treatment. Combined administration of two or more drugs is a new strategy in the treatment of breast cancer. Comparing combination therapy to monotherapy, the therapeutic effect is greater and the side effects are less because the drugs used in combination therapy affect the cell through various mechanisms. Capecitabine is a DNA/RNA synthesis inhibitor and is used in many cancer treatments. Mocetinostat is an HDACi and has effects on apoptosis, differentiation, cell cycle involvement, inhibition of DNA repair, oxidative stress and autophagy. The aim of this study is to investigate the effect of using Capecitabine, Mocetinostat, Capecitabine+ Mocetinostat in the treatment of breast cancer on the mechanism of apoptosis both in vivo and in vitro.4T1 breast cancer cell line is very similar to human TNBC, it is widely used in in vivo breast cancer research. In the in vitro part of the study, the IC50 value of single and combined drug doses was determined. Then survival, DNA laddering, wound healing and western blot testing were performed. In the in vivo part of the study, 4T1 cells were injected into BALB/c mice to form mammary tumors. Tumor and lung tissues taken from animals were examined histologically and immunochemically. According to the results obtained, the combined treatment was more effective at low doses than the single treatment and showed a very strong cytotoxic effect on the cells. In addition, the level of Bcl-2, HDACI, AKT, PI3K, C-myc, HDACIII proteins, which are involved in the apoptotic pathway, were significantly decreased and the level of Bax, Caspase-3, PTEN, Caspase-7, Caspase-9, p53 proteins was increased by combine treatment of Capecitabine and Mocetinostat.