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肝胆相照论坛 论坛 学术讨论& HBV English 一种新型Smac模拟APG-1387通过诱导细胞凋亡和增强天然抗 ...
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一种新型Smac模拟APG-1387通过诱导细胞凋亡和增强天然抗肿瘤

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62111 元 
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30441 
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2009-10-5 
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2022-12-28 

才高八斗

发表于 2018-4-23 05:56 |显示全部帖子
Biochem Pharmacol. 2018 Apr 18. pii: S0006-2952(18)30163-1. doi: 10.1016/j.bcp.2018.04.020. [Epub ahead of print]
A Novel Smac Mimetic APG-1387 Exhibited Dual Antitumor Effect on HBV-positive Hepatocellular Carcinoma with High Expression of cIAP2 by Inducing Apoptosis and Enhancing Innate Anti-Tumor Immunity.Pan W1, Luo Q1, Yan X1, Yuan L1, Yi H1, Zhang L2, Li B1, Zhang Y1, Sun J3, Qiu MZ4, Yang DJ5.
Author information
1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 51000, PR China; Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, PR China.2State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 51000, PR China; Department of Clinical Laboratory, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, PR China.3State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 51000, PR China; Department of Clinical Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, PR China. Electronic address: [email protected].4State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 51000, PR China; Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, PR China. Electronic address: [email protected].5State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 51000, PR China; Suzhou Ascentage Pharma Inc., Jiangsu 215123, China. Electronic address: [email protected].

AbstractCheck point inhibitor anti-PD1 antibody produced some efficacy in Hepatocellular Carcinoma (HCC) patients previously treated with sorafenib. Unfortunately, HCC patients with hepatitis B virus (HBV) infection did not respond as well as uninfected patients. Previously, SMAC mimetics-the antagonist for inhibitor of apoptosis proteins (IAPs) can rapidly reduce serum hepatitis B virus DNA in animal model. APG-1387 is a novel SMAC-mimetic, small molecule inhibitor targeting inhibitor of apoptosis proteins (IAPs). In our study, firstly, we found that HCC patients with copy number alteration of cIAP1, cIAP2, and XIAP had a dismal prognosis. Then, we discovered that APG-1387 alone could induce apoptosis of PLC/PRF/5 which was HBV positive both in-vitro and in-vivo. Furthermore, we found that APG-1387 significantly up-regulated the expression of calreticulin and HLA-DR in PLC/PRF/5 via activating non-classic NF-κB pathway. Also, compared to vehicle group, APG-1387 increased NK cell counts by 5 folds in PLC/PRF/5 xenograft model. In-vitro, APG-1387 positively regulated T cells by reducing Treg differentiation and down-regulating PD1 expression in CD4 T cell. Moreover, APG-1387 had no impact on memory T cells. Consequently, our results suggest that APG1387 could be a good candidate to combine with anti-PD1 antibody treatment to overcome low responds of check point inhibitors in HBV positive HCC.


KEYWORDS: Apoptosis; Check point inhibitors; Hepatitis B virus; Hepatocellular carcinoma; Smac-mimetic

PMID:29679556DOI:10.1016/j.bcp.2018.04.020

Rank: 8Rank: 8

现金
62111 元 
精华
26 
帖子
30441 
注册时间
2009-10-5 
最后登录
2022-12-28 

才高八斗

发表于 2018-4-23 05:56 |显示全部帖子
Biochem Pharmacol。 2018年4月18日。pii:S0006-2952(18)30163-1。 doi:10.1016 / j.bcp.2018.04.020。 [电子版提前打印]
一种新型Smac模拟APG-1387通过诱导细胞凋亡和增强天然抗肿瘤免疫表现出双重抗肿瘤效应,对HBV阳性肝细胞癌具有高表达cIAP2。
Pan W1,Luo Q1,Yan X1,Yuan L1,Yi H1,Zhang L2,Li B1,Zhang Y1,Sun J3,Qiu MZ4,Yang DJ5。
作者信息
抽象

检查点抑制剂抗PD1抗体在先前用索拉非尼治疗的肝细胞癌(HCC)患者中产生一些功效。不幸的是,乙型肝炎病毒(HBV)感染的HCC患者与未感染的患者一样没有反应。以前,SMAC模拟物 - 凋亡蛋白抑制剂(IAPs)的拮抗剂可以在动物模型中快速降低血清乙型肝炎病毒DNA。 APG-1387是一种新型SMAC模拟物,靶向凋亡蛋白抑制剂(IAPs)的小分子抑制剂。在我们的研究中,首先发现cIAP1,cIAP2和XIAP拷贝数改变的HCC患者预后不良。然后,我们发现单独使用APG-1387可诱导体外和体内HBV阳性的PLC / PRF / 5的凋亡。此外,我们发现APG-1387通过激活非经典NF-κB途径显着上调PLC / PRF / 5中钙网蛋白和HLA-DR的表达。此外,与载体组相比,APG-1387在PLC / PRF / 5异种移植模型中使NK细胞计数增加了5倍。在体外,APG-1387通过减少Treg分化和下调CD4 T细胞中的PD1表达来正向调节T细胞。此外,APG-1387对记忆T细胞没有影响。因此,我们的研究结果表明APG1387可能是结合抗PD1抗体治疗以克服HBV阳性HCC中的检查点抑制剂的低反应的良好候选者。
关键词:

细胞凋亡;检查点抑制剂;乙型肝炎病毒;肝细胞癌; SMAC-模拟

结论:
    29679556
DOI:
    10.1016 / j.bcp.2018.04.020
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