ARV-825在胃癌的MYC靶点和G2M检查点信号通路中显示出抗肿瘤活性。
ARV-825 Demonstrates Antitumor Activity in Gastric Cancer MYC-Targets and G2M-Checkpoint Signaling Pathways.
作者信息
Liao Xinmei, Qian Xiaoqing, Zhang Zimu, Tao Yanfang, Li Zhiheng, Zhang Qian, Liang Hui, Li Xiaolu, Xie Yi, Zhuo Ran, Chen Yanling, Jiang You, Cao Haibo, Niu Jiaqi, Xue Cuili, Ni Jian, Pan Jian, Cui Daxiang
机构信息
Institute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, China.
School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
出版信息
Front Oncol. 2021 Oct 18;11:753119. doi: 10.3389/fonc.2021.753119. eCollection 2021.
OBJECTIVE
Suppression of bromodomain and extra terminal (BET) proteins has a bright prospect to treat MYC-driven tumors. Bromodomain containing 4 (BRD4) is one of the BET proteins. ARV-825, consisting of a BRD4 inhibitor conjugated with a cereblon ligand using proteolysis-targeting chimera (PROTAC) technology, was proven to decrease the tumor growth effectively and continuously. Nevertheless, the efficacy and mechanisms of ARV-825 in gastric cancer are still poorly understood.
METHODS
Cell counting kit 8 assay, lentivirus infection, Western blotting analysis, Annexin V/propidium iodide (PI) staining, RNA sequencing, a xenograft model, and immunohistochemistry were used to assess the efficacy of ARV-825 in cell level and animal model.
RESULTS
The messenger RNA (mRNA) expression of 4 in gastric cancer raised significantly than those in normal tissues, which suggested poor outcome of patients with gastric cancer. ARV-825 displayed higher anticancer efficiency in gastric cancer cells than OTX015 and JQ1. ARV-825 could inhibit cell growth, inducing cell cycle block and apoptosis . ARV-825 induced degradation of BRD4, BRD2, BRD3, c-MYC, and polo-like kinase 1 (PLK1) proteins in four gastric cancer cell lines. In addition, cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP) was elevated. Knockdown or overexpression could increase or decrease, respectively, the ARV-825 IC50 of gastric cancer cells. ARV-825 reduced and expression in gastric cancer cells. ARV-825 treatment significantly reduced tumor growth without toxic side effects and downregulated the expression of BRD4 .
CONCLUSIONS
High mRNA expression of in gastric cancer indicated poor prognosis. ARV-825, a BRD4 inhibitor, could effectively suppress the growth and elevate the apoptosis of gastric cancer cells transcription downregulation of c-MYC and PLK1. These results implied that ARV-825 could be a good therapeutic strategy to treat gastric cancer.
目的
抑制含溴结构域和额外末端（BET）蛋白在治疗MYC驱动的肿瘤方面前景光明。含溴结构域蛋白4（BRD4）是BET蛋白之一。ARV - 825由一种BRD4抑制剂与一个通过蛋白酶靶向嵌合体（PROTAC）技术连接的cereblon配体组成，已被证明能有效且持续地抑制肿瘤生长。然而，ARV - 825在胃癌中的疗效和机制仍知之甚少。
方法
采用细胞计数试剂盒8检测、慢病毒感染、蛋白质印迹分析、膜联蛋白V/碘化丙啶（PI）染色、RNA测序、异种移植模型和免疫组织化学来评估ARV - 825在细胞水平和动物模型中的疗效。
结果
胃癌中4的信使核糖核酸（mRNA）表达显著高于正常组织，这表明胃癌患者预后不良。ARV - 825在胃癌细胞中显示出比OTX015和JQ1更高的抗癌效率。ARV - 825可抑制细胞生长，诱导细胞周期阻滞和凋亡。ARV - 825诱导四种胃癌细胞系中BRD4、BRD2、BRD3、c - MYC和polo样激酶1（PLK1）蛋白的降解。此外，半胱天冬酶3和聚ADP核糖聚合酶（PARP）的切割增加。敲低或过表达分别可增加或降低胃癌细胞的ARV - 825半数抑制浓度（IC50）。ARV - 825降低了胃癌细胞中的 和 表达。ARV - 825治疗显著降低肿瘤生长且无毒性副作用，并下调了BRD4的表达。
结论
胃癌中 的高mRNA表达表明预后不良。ARV - 825作为一种BRD4抑制剂，可通过下调c - MYC和PLK1转录有效抑制胃癌细胞生长并促进其凋亡。这些结果表明ARV - 825可能是治疗胃癌的一种良好治疗策略。
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