Enhancement of the proapoptotic properties of newcastle disease virus promotes tumor remission in syngeneic murine cancer models.
Enhancement of the proapoptotic properties of newcastle disease virus promotes tumor remission in syngeneic murine cancer models.
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DOI：
10.1158/1535-7163.mct-14-0913
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发表时间：
2015-05
影响因子：
5.7
通讯作者：
Villar E
中科院分区：
文献类型：
--
作者：
Cuadrado-Castano S;Ayllon J;Mansour M;de la Iglesia-Vicente J;Jordan S;Tripathi S;García-Sastre A;Villar E
纽卡斯尔病病毒（NDV）具有溶瘤特性，被认为是一种很有前途的肿瘤治疗药物。这些包括转化细胞中的优先复制、肿瘤内先天性和适应性免疫应答的诱导以及由于细胞凋亡的激活而在感染的肿瘤细胞中的细胞病变效应。为了增强后者，从而可能提高NDV的整体溶瘤活性，我们产生了编码人TNF受体Fas的重组NDV（rNDV-B1/Fas）。rNDV-B1/Fas复制到与其野生型（rNDV-B1）对应物相似的滴度，然而Fas在感染细胞中的过表达导致更高水平的细胞毒性，其与更快和增加的凋亡反应相关，其中内源性和外源性途径都被更早地激活。此外，在同基因小鼠黑色素瘤模型中的体内研究显示rNDV-B1/Fas的溶瘤特性增强，存活率和肿瘤缓解显著改善。总之，我们的数据表明，上调NDV的促细胞凋亡功能是增强其抗肿瘤特性的可行方法，并增加了目前已知的基于合理的策略来设计用于治疗癌症的优化治疗性病毒载体。
Newcastle disease virus (NDV) is considered a promising agent for cancer therapy due to its oncolytic properties. These include preferential replication in transformed cells, induction of innate and adaptive immune responses within tumors and cytopathic effects in infected tumor cells due to the activation of apoptosis. In order to enhance the latter and thus possibly enhance the overall oncolytic activity of NDV, we generated a recombinant NDV encoding the human TNF receptor Fas (rNDV-B1/Fas). rNDV-B1/Fas replicates to similar titers as its wild type (rNDV-B1) counterpart, however overexpression of Fas in infected cells leads to higher levels of cytotoxicity correlated with faster and increased apoptosis responses in which both the intrinsic and extrinsic pathways are activated earlier. Furthermore, in vivo studies in syngeneic murine melanoma model show an enhancement of the oncolytic properties of rNDV-B1/Fas, with major improvements in survival and tumor remission. Altogether, our data suggest that up-regulation of the pro-apoptotic function of NDV is a viable approach to enhance its anti-tumor properties, and adds to the currently known, rationally-based strategies to design optimized therapeutic viral vectors for the treatment of cancer.