RETRACTED ARTICLE: The BET inhibitor I-BET762 inhibits pancreatic ductal adenocarcinoma cell proliferation and enhances the therapeutic effect of gemcitabine

Fang Xie,Mei Huang,Xiansheng Lin,Chenhai Liu,Zhen Liu,Futao Meng,Chao Wang,Qiang Huang

doi:10.1038/s41598-018-26496-0

Fang Xie, Mei Huang + Show 6 more

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https://doi.org/10.1038/s41598-018-26496-0

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Journal: Scientific Reports	Publication Date: May 25, 2018
Citations: 30	License type: open-access

Affiliation: Anhui Provincial Hospital

Abstract

As one of the most fatal malignancies, pancreatic ductal adenocarcinoma (PDAC) has significant resistance to the currently available treatment approaches. Gemcitabine, the standard chemotherapeutic agent for locally advanced and metastatic PDAC, has limited efficacy, which is attributed to innate/acquired resistance and the activation of prosurvival pathways. Here, we investigated the in vitro efficacy of I-BET762, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, in treating PDAC cell lines alone and in combination with gemcitabine (GEM). The effect of these two agents was also examined in xenograft PDAC tumors in mice. We found that I-BET762 induced cell cycle arrest in the G0/G1 phase and cell death and suppressed cell proliferation and metastatic stem cell factors in PDAC cells. In addition, the BH3-only protein Bim, which is related to chemotherapy resistance, was upregulated by I-BET762, which increased the cell death triggered by GEM in PDAC cells. Moreover, GEM and I-BET762 exerted a synergistic effect on cytotoxicity both in vitro and in vivo. Furthermore, Bim is necessary for I-BET762 activity and modulates the synergistic effect of GEM and I-BET762 in PDAC. In conclusion, we investigated the effect of I-BET762 on PDAC and suggest an innovative strategy for PDAC treatment.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is the 12th most prevalent malignancy worldwide[1]
To determine the influence of bromodomain and extraterminal (BET) inhibitors, pancreatic ductal adenocarcinoma (PDAC) cells were treated with JQ-1 and I-BET762
The results revealed that I-BET762 and JQ-1 noticeably triggered apoptosis in PDAC cells (Fig. 1D)

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the 12th most prevalent malignancy worldwide[1]. Twenty percent of patients receiving a diagnosis of PDAC qualify for surgery[6]. The five-year survival rates for patients with PDAC after surgical resection are only approximately twenty percent, even with GEM supplementation[13]. The bromodomain and extraterminal (BET) family participates in recognizing ε-N-acetylated lysine residues in histone tails[14]. Other mediators besides BRD4 co-occupy the promoters and enhancers of stimulated genes[16] These mediators are enriched at numerous enhancer sequences, commonly named superenhancers[17]. Study has shown that I-BET762 downregulates c-Myc, and dephosphorylation of ERK1/2 leading to proliferation inhibition in pancreatic cancer cells[23]. The influence of BET inhibitors together with GEM on PDAC was explored both in vitro and in vivo

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Results

Conclusion