PI3K/mTOR dual inhibitor BEZ235 and histone deacetylase inhibitor Trichostatin A synergistically exert anti-tumor activity in breast cancer

• Published in: Oncotarget 2017-02, Vol.8 (7), p.11937-11949
• Main Authors: Chen, Liyan, Jin, Tiefeng, Zhu, Kun, Piao, Yingshi, Quan, Taihao, Quan, Chunji, Lin, Zhenhua
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; Autophagy - drug effects; Breast Neoplasms - drug therapy; Breast Neoplasms - enzymology; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Synergism; Female; Histone Deacetylase Inhibitors - administration & dosage; Histone Deacetylase Inhibitors - pharmacology; Humans; Hydroxamic Acids - administration & dosage; Hydroxamic Acids - pharmacology; Hydroxamic Acids - therapeutic use; Imidazoles - administration & dosage; Imidazoles - pharmacology; MCF-7 Cells; Mice; Mice, Nude; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Quinolines - administration & dosage; Quinolines - pharmacology; Research Paper; Signal Transduction; TOR Serine-Threonine Kinases - antagonists & inhibitors; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.14442

Molecule-targeted therapy has achieved great progress in cancer therapy. Effective drug combinations are one way to enhance the therapeutic efficacy and combat resistance. Here, we determined the effect of the PI3K/mTOR dual inhibitor BEZ235 and the histone deacetylase inhibitor Trichostatin A (TSA) on human breast cancer. We demonstrated that the combination of BEZ235 and TSA results in significant synergistic growth inhibition of multiple breast cancer cell lines. Mechanistic studies revealed that the combined therapy induced apoptosis in a caspase-dependent manner, which might be related to the further depression of the PI3K/Akt/mTOR signalling pathway. Additionally, co-treatment with BEZ235 and TSA enhanced autophagic cell death by up-regulating the expression of LC3B-II and Beclin-1. The vivo tumour modelling studies revealed that BEZ235 combined with TSA blocked tumour growth without noticeable side effects. These data suggest that the combination of BEZ235 and TSA may be a new selective strategy, which may have significant clinical application in the treatment of breast cancer patients.