Weiqiang Zhou*, Han Han, Junnan Xu, Tao Sun* and Xiuyan Feng* Pages 2366 - 2380 ( 15 )
Background: Breast cancer is one of the most prevalent diseases threatening women's health today. Indepth research on breast cancer (BC) pathogenesis and prevention and treatment methods are gradually receiving attention. Chidamide is a novel histone deacetylase inhibitor (HDACi) that depresses the function of histone deacetylase, consequently affecting the growth of BC cells through epigenetic modification. However, preclinical and clinical studies show that chidamide is ineffective in long-term treatment. We demonstrated in previous experiments that TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in BC cells and is significantly less non-toxic to normal cells than chidamide. Therefore, in this study, we treated BC cells with chidamide and TRAIL to explore a novel option to reduce the clinical toxicity through augmenting the sensitivity for BC cells.
Methods and Results: Results from the MTT and cell viability assays indicated that the combination of chidamide and TRAIL in MCF-7 and MDA-MB-231 cells induced BC cell death, while maintaining a reduced concentration of chidamide. Autophagy assay and annexin V analysis showed that the autophagosome microtubuleassociated protein1light chain3-II (LC3-II) was abnormally increased and much more early and late phase of apoptotic cells appeared during chidamide and TRAIL induction. Anti-tumor assays in a BC tumor xenograft model displayed that the mixture of chidamide and TRAIL exhibited stronger effects on inhibiting tumor growth. The data from real-time PCR and western blotting showed that the cytotoxic effect correlated with the expressions of related apoptosis and autophagy factors.
Conclusion: Our data are the first to demonstrate the synergistic effects of chidamide and TRAIL in BC cells, specifically, the pharmacological effects on cell death induction. These results lay a solid experimental and theoretical basis to solve the clinical resistance of chidamide.
Chidamide, TRAIL, apoptosis, drug resistance, breast cancer, HDACi.
Department of Pathogen Biology, Shenyang Medical College, No. 146 North Huanghe St, Huanggu Dis, Shenyang City, Liaoning Pro 110034, Department of Biochemistry and Molecular Biology, Shenyang Medical College, No. 146 North Huanghe St, Huanggu Dis, Shenyang City, Liaoning Pro 110034, Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and & Institute, Key Laboratory of Liaoning Breast Cancer Research, No. 44 Xiaoheyan Rd, Dadong Dis, Shenyang City, Liaoning Pro 110042, Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and & Institute, Key Laboratory of Liaoning Breast Cancer Research, No. 44 Xiaoheyan Rd, Dadong Dis, Shenyang City, Liaoning Pro 110042, The Second Affiliated Hospital of Shenyang Medical College, No.20 North 9th St, Heping Dis, Shenyang City, Liaoning Pro 110002