Synergistic effects of combined treatment with histone deacetylase inhibitor suberoylanilide hydroxamic acid and TRAIL on human breast cancer cells.

Weiqiang Zhou,Guangdi Wang,Xiuyan Feng,Han Han Han Han,Shanchun Guo

doi:10.1038/srep28004

Abstract

Previous studies showed that either histone deacetylase (HDAC) inhibitors or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in tumor cells including breast cancer. However, the underling mechanisms of combining HDAC inhibitors with TRAIL in the treatment of breast cancer are poorly understood. In this study, we determined the ability of SAHA and TRAIL as single agents or in combination to inhibit the growth and survival of MCF-7 and MDA-MB-231 breast cancer cells. Our results demonstrate that the distinct effects of SAHA or TRAIL individually and in combination on the proliferation, cell viability, apoptosis, cell cycle distribution, and morphological changes of MDA-MB-231 and MCF-7 cells. We further determined the different effects of SAHA or TRAIL alone and combining SAHA with TRAIL on the expression of a number of apoptosis-related molecules, cell cycle, growth factors and their receptors in cancer cells. Our results demonstrated that the combinatorial treatment of SAHA and TRAIL may target multiple pathways and serve as an effective therapeutic strategy against breast cancer. An improved understanding of the molecular mechanisms may facilitate either SAHA or TRAIL targeted use and the selection of suitable combinations.

Highlights

Large number of ongoing clinical trials to evaluate its utility in treating various solid tumors
We first evaluated the effects exerted by Suberanilohydroxamic acid (SAHA) in a triple negative breast cancer cell model, MDA-MB-231 and an estrogen receptor (ER)+MCF-7 cell lines
We found that SAHA treatment induced a time- and dose-dependent decrease in cell index (CI) values in both cell lines

Summary

Introduction

Large number of ongoing clinical trials to evaluate its utility in treating various solid tumors. Studies have shown that SAHA can induce apoptosis and growth arrest in breast cancer cell lines including MCF-7, MDA-MB-231, MDA-MB-435, MDA-MB-468, and SKBr-315–19. TRAIL preferentially induces apoptosis in tumor cell lines that lack DcR1, DcR2, but not in normal cells which express DcR1, DcR2, suggesting that TRAIL could potentially represent a powerful cancer therapeutic[32,33]. TRAIL-based combinatorial therapies are emerging paradigms for cancer treatment since synergistic activation of TRAIL-induced apoptosis by chemotherapeutic drugs can generally overcome tumor cell resistance, while monotherapies are often fail. A number of preclinical studies combining HDAC inhibitors with TRAIL have shown synergistic effects in inhibition of proliferation and induction of apoptosis in tumor cells[36]. We sought to characterize the effects of combining SAHA with TRAIL on the regulation of breast cancer genes, related signaling pathways, and morphology

Objectives

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Conclusion