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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
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