Oncolytic Group B Adenovirus Enadenotucirev Mediates Non-apoptotic Cell Death with Membrane Disruption and Release of Inflammatory Mediators.
Oncolytic Group B Adenovirus Enadenotucirev Mediates Non-apoptotic Cell Death with Membrane Disruption and Release of Inflammatory Mediators.
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DOI：
10.1016/j.omto.2016.11.003
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发表时间：
2017-03-17
期刊：
影响因子：
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通讯作者：
Seymour LW
中科院分区：
文献类型：
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作者：
Dyer A;Di Y;Calderon H;Illingworth S;Kueberuwa G;Tedcastle A;Jakeman P;Chia SL;Brown A;Silva MA;Barlow D;Beadle J;Hermiston T;Ferguson DJ;Champion B;Fisher KD;Seymour LW
Enadenotucirev（EnAd）是通过生物选择从腺病毒血清型文库分离的嵌合B组腺病毒。它选择性地复制并杀死各种癌细胞，在临床前系统中显示出有效的抗癌活性，目前正在进行I/II期临床试验。EnAd比5型腺病毒更快地杀死细胞，并且细胞毒性的速度是剂量依赖性的。EnAd死亡途径不涉及p53，主要是半胱天冬酶非依赖性的，并且似乎涉及细胞ATP的快速下降。感染的细胞表现出膜完整性的早期丧失;钙网蛋白的暴露增加; ATP、HSP 70和HMGB 1的细胞外释放;以及钙的内流。该病毒还引起一个明显的单膜水泡，使人联想到由胀亡引起的缺血性细胞死亡。在维持在离体培养物中的人肿瘤活检中，EnAd介导促炎介质如TNF-α、IL-6和HMGB 1的释放。与此一致，EnAd感染的肿瘤细胞在体外混合肿瘤-白细胞反应中显示出对树突状细胞和CD 4 + T细胞的有效刺激。尽管许多病毒已经进化为具有最小炎症的有效繁殖，但用于快速杀伤的EnAd的生物选择已经产生了具有短生命周期的病毒，其将有效的细胞毒性与细胞死亡的促炎机制相结合。
Enadenotucirev (EnAd) is a chimeric group B adenovirus isolated by bioselection from a library of adenovirus serotypes. It replicates selectively in and kills a diverse range of carcinoma cells, shows effective anticancer activity in preclinical systems, and is currently undergoing phase I/II clinical trials. EnAd kills cells more quickly than type 5 adenovirus, and speed of cytotoxicity is dose dependent. The EnAd death pathway does not involve p53, is predominantly caspase independent, and appears to involve a rapid fall in cellular ATP. Infected cells show early loss of membrane integrity; increased exposure of calreticulin; extracellular release of ATP, HSP70, and HMGB1; and influx of calcium. The virus also causes an obvious single membrane blister reminiscent of ischemic cell death by oncosis. In human tumor biopsies maintained in ex vivo culture, EnAd mediated release of pro-inflammatory mediators such as TNF-α, IL-6, and HMGB1. In accordance with this, EnAd-infected tumor cells showed potent stimulation of dendritic cells and CD4+ T cells in a mixed tumor-leukocyte reaction in vitro. Whereas many viruses have evolved for efficient propagation with minimal inflammation, bioselection of EnAd for rapid killing has yielded a virus with a short life cycle that combines potent cytotoxicity with a proinflammatory mechanism of cell death.