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

Liyan Chen,Kun Zhu,Yingshi Piao,Tiefeng Jin,Chunji Quan,Zhenhua Lin,Taihao Quan

doi:10.18632/oncotarget.14442

Liyan Chen, Kun Zhu + Show 5 more

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https://doi.org/10.18632/oncotarget.14442

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Abstract

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.

Highlights

Breast cancer is the second major cause of cancer-related death for women in world-wide [1]
Recent studies indicate that combined PI3K/mTOR inhibitor with histone deacetylase (HDAC) inhibitor may be more efficacious than single drug in some cancer cells [25,26]
Erlich et al reported that the PI3K/mTOR inhibitor BGT226 (Novartis) and BEZ235, in combination with the HDAC inhibitor panobinostat, inhibit the viability of head and neck squamous carcinoma cells better than single drug [27]

Summary

Introduction

Breast cancer is the second major cause of cancer-related death for women in world-wide [1]. The phosphoinositol-3-kinase/serine-threonine protein kinase B/mammalian target of rapamycin (PI3K/ Akt/mTOR) signalling pathway, which plays important biological roles in normal cellular physiology, has been demonstrated to be activated in breast cancer [3,4]. 25% of breast cancer tumours have mutations in the gene encoding the kinase active p110α subunit of PI3K (PIK3CA), with the majority of mutations located in the kinase domain. The expression of phosphorylated 4EBP1, a downstream effector of PI3K in breast tumour specimens, has been associated with poor prognosis [7]. These findings have encouraged the development of several different inhibitors targeting the PI3K/Akt/mTOR pathway, many of which are either in or approaching clinical trials [8,9]. In www.impactjournals.com/oncotarget combined treatments with melphalan, doxorubicin, and bortezomib, BEZ235 showed synergistic and additive effects on cell growth inhibition in multiple cancer cells [13,14], suggesting its potential clinical activity combined with chemotherapeutic agents

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