ARV-825 Demonstrates Antitumor Activity in Gastric Cancer via MYC-Targets and G2M-Checkpoint Signaling Pathways.
ARV-825 Demonstrates Antitumor Activity in Gastric Cancer via MYC-Targets and G2M-Checkpoint Signaling Pathways.
复制标题
ARV-825 通过 MYC 靶标和 G2M 检查点信号通路展示对胃癌的抗肿瘤活性。
DOI：
10.3389/fonc.2021.753119
复制
发表时间：
2021
影响因子：
4.7
通讯作者：
Cui D
中科院分区：
文献类型：
--
作者：
Liao X;Qian X;Zhang Z;Tao Y;Li Z;Zhang Q;Liang H;Li X;Xie Y;Zhuo R;Chen Y;Jiang Y;Cao H;Niu J;Xue C;Ni J;Pan J;Cui D
抑制布罗莫结构域和额外末端（BET）蛋白对于治疗MYC驱动的肿瘤具有光明的前景。含溴结构域4（BRD4）是BET蛋白之一。ARV-825由使用蛋白水解靶向嵌合体（PROTAC）技术与cereblon配体缀合的BRD 4抑制剂组成，被证明有效且持续地降低肿瘤生长。然而，ARV-825在胃癌中的疗效和机制仍然知之甚少。采用细胞计数试剂盒8法、慢病毒感染法、蛋白质印迹法、Annexin V/碘化丙啶（PI）染色法、RNA测序法、异种移植模型和免疫组织化学法评估ARV-825在细胞水平和动物模型中的疗效。BRD4 mRNA在胃癌组织中的表达明显高于正常组织，提示胃癌患者预后不良。ARV-825在胃癌细胞中显示出比OTX015和JQ1更高的抗癌效率。ARV-825在体外可抑制细胞生长，诱导细胞周期阻滞和凋亡。ARV-825在四种胃癌细胞系中诱导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）的切割升高。CRBN基因敲除或过表达可分别增加或降低胃癌细胞ARV-825的IC 50。ARV-825降低胃癌细胞MYC和PLK1的表达。ARV-825治疗显着减少肿瘤生长，没有毒副作用，并下调BRD4的表达在体内。BRD4 mRNA在胃癌中的高表达提示预后不良。BRD4抑制剂ARV-825可通过下调c-MYC和PLK1的转录水平，有效抑制胃癌细胞的生长并促进其凋亡。这些结果表明，ARV-825可能是一个很好的治疗胃癌的策略。
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. 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. The messenger RNA (mRNA) expression of BRD4 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 in vitro. 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 CRBN could increase or decrease, respectively, the ARV-825 IC50 of gastric cancer cells. ARV-825 reduced MYC and PLK1 expression in gastric cancer cells. ARV-825 treatment significantly reduced tumor growth without toxic side effects and downregulated the expression of BRD4 in vivo. High mRNA expression of BRD4 in gastric cancer indicated poor prognosis. ARV-825, a BRD4 inhibitor, could effectively suppress the growth and elevate the apoptosis of gastric cancer cells via transcription downregulation of c-MYC and PLK1. These results implied that ARV-825 could be a good therapeutic strategy to treat gastric cancer.
登录
查看更多内容
纳米颗粒负载的极化巨噬细胞用于增强肿瘤靶向和细胞化疗
影响因子：
26.6
作者：
Hou T;Wang T;Mu W;Yang R;Liang S;Zhang Z;Fu S;Gao T;Liu Y;Zhang N
通讯作者：
Zhang N
影响因子：
12.4
作者：
Liu, Mei;Wang, Zhifei;He, Nongyue
通讯作者：
He, Nongyue
影响因子：
14.8
作者：
Bondeson DP;Mares A;Smith IE;Ko E;Campos S;Miah AH;Mulholland KE;Routly N;Buckley DL;Gustafson JL;Zinn N;Grandi P;Shimamura S;Bergamini G;Faelth-Savitski M;Bantscheff M;Cox C;Gordon DA;Willard RR;Flanagan JJ;Casillas LN;Votta BJ;den Besten W;Famm K;Kruidenier L;Carter PS;Harling JD;Churcher I;Crews CM
通讯作者：
Crews CM
PF-3758309（一种针对 p21 激活激酶 4 的小分子抑制剂）抑制神经母细胞瘤增殖
影响因子：
4.2
作者：
Li Z;Li X;Xu L;Tao Y;Yang C;Chen X;Fang F;Wu Y;Ding X;Zhao H;Li M;Qian G;Xu Y;Ren J;Du W;Wang J;Lu J;Hu S;Pan J
通讯作者：
Pan J
影响因子：
9
作者：
Dong X;Hu X;Chen J;Hu D;Chen LF
通讯作者：
Chen LF