Chen Liyan, Jin Tiefeng, Zhu Kun, Piao Yingshi, Quan Taihao, Quan Chunji, Lin Zhenhua
Department of Pathology and Cancer Research Center, Yanbian University Medical College, Yanji 133002, China.
Department of Biochemistry and Molecular Biology, Yanbian University Medical College, Yanji 133002, China.
Oncotarget. 2017 Feb 14;8(7):11937-11949. 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.
分子靶向治疗在癌症治疗方面已取得巨大进展。有效的药物联合是提高治疗效果和对抗耐药性的一种方法。在此，我们确定了PI3K/mTOR双重抑制剂BEZ235和组蛋白去乙酰化酶抑制剂曲古抑菌素A（TSA）对人乳腺癌的作用。我们证明，BEZ235与TSA联合使用可对多种乳腺癌细胞系产生显著的协同生长抑制作用。机制研究表明，联合治疗以半胱天冬酶依赖性方式诱导细胞凋亡，这可能与PI3K/Akt/mTOR信号通路的进一步抑制有关。此外，BEZ235与TSA联合处理通过上调LC3B-II和Beclin-1的表达增强了自噬性细胞死亡。体内肿瘤建模研究表明，BEZ235与TSA联合使用可阻断肿瘤生长且无明显副作用。这些数据表明，BEZ235与TSA联合使用可能是一种新的选择性策略，在乳腺癌患者的治疗中可能具有重要的临床应用价值。
