The synergistic anticancer effect of the bromodomain inhibitor OTX015 and histone deacetylase 6 inhibitor WT-161 in osteosarcoma

Bo Yu,Zhengzai Dai,Yuanxiang Peng,Teng Li,Qi Liao,Feifei Zhang,Yiping Liang,Duo Zeng,Xiao-Bin Lv,Xuhui Yuan,Feng Cai,Lang Liu,Jiayu Li,Xiaofeng Tang

doi:10.1186/s12935-022-02443-y

Abstract

BackgroundOsteosarcoma (OS) is a tumour with a high malignancy level and a poor prognosis. First-line chemotherapy for OS has not been improved for many decades. Bromodomain and extraterminal domain (BET) and histone deacetylases (HDACs) regulate histone acetylation in tandem, and BET and HDACs have emerged as potential cancer therapeutic targets.MethodsCell proliferation, migration, invasion, colony formation, and sphere-forming assays were performed with the two inhibitors alone or in combination to evaluate their suppressive effect on the malignant properties of OS cells. Apoptosis and the cell cycle profile were measured by flow cytometry. The synergistic inhibitory effect of OTX015/WT-161 on tumours was also examined in a nude mouse xenograft model.ResultsThe combined therapy of OTX015/WT-161 synergistically inhibited growth, migration, and invasion and induced apoptosis, resulting in G1/S arrest of OS cells. Additionally, OTX015/WT-161 inhibited the self-renewal ability of OS stem cells (OSCs) in a synergistic manner. Further mechanistic exploration revealed that the synergistic downregulation of β-catenin by OTX015-mediated suppression of FZD2 and WT-161-mediated upregulation of PTEN may be critical for the synergistic effect. Finally, the results of an in vivo assay showed that tumour xenografts were significantly decreased after treatment with the OTX015/WT-161 combination compared with OTX015 or WT-161 alone.ConclusionsOur findings in this study demonstrated that OTX015 and WT-161 had synergistic anticancer efficacy against OS, and their combination might be a promising therapeutic strategy for OS.

Highlights

OS is the most common malignant bone tumour
We demonstrated the synergistic effect of the bromodomain inhibitor OTX015 and HDAC6 inhibitor WT-161 in killing OS
Cotreatment with OTX015 and WT‐161 inhibitors inhibits OS cell growth in a synergistic manner First, OS cell lines (MG63, U2OS) were exposed to increasing concentrations of OTX015 or WT-161 inhibitors for 24, 48, or 72 h, and OS cell proliferation was measured by the CCK-8 assay

Summary

Introduction

OS is the most common malignant bone tumour It mainly affects children and young adults, with an incidence peak at approximately 18 years old, and is mostly localized in long bones [1]. Due to the characteristics of early metastasis and poor prognosis of OS, this aggressive malignant tumour has become a major cause of death, threatening adolescents and young adults. Bromodomain and extraterminal family proteins (BRDT, BRD2, BRD3, and BRD4), as chromatin readers, bind to acetylated lysine residues on histones [4]. The N-terminal bromodomain of BRD4 recognizes acetylated lysine on nucleosome histones, and BRD4 interacts with P-TEFb (positive transcription elongation Factor b) to facilitate the transcription of several oncogenes, such as c-myc, which contribute to the proliferation of cancer cells [5, 6]. Bromodomain and extraterminal domain (BET) and histone deacetylases (HDACs) regulate histone acetylation in tandem, and BET and HDACs have emerged as potential cancer therapeutic targets

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