Suppression of Oncolytic Adenovirus-Mediated Hepatotoxicity by Liver-Specific Inhibition of NF-κB.
Suppression of Oncolytic Adenovirus-Mediated Hepatotoxicity by Liver-Specific Inhibition of NF-κB.
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DOI：
10.1016/j.omto.2017.10.003
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发表时间：
2017-12-15
期刊：
影响因子：
--
通讯作者：
Mizuguchi H
中科院分区：
文献类型：
--
作者：
Machitani M;Sakurai F;Wakabayashi K;Nakatani K;Tachibana M;Kato N;Fujiwara T;Mizuguchi H
端粒酶特异性可复制腺病毒（Ads），即，TRADs具有由人端粒酶逆转录酶启动子驱动的E1基因表达盒，是有希望的癌症治疗剂。然而，即使肿瘤内施用溶瘤Ad（包括TRAD），它们也从肿瘤扩散到体循环，引起对溶瘤Ad介导的肝毒性的关注（主要由于Ad基因在肝脏中的泄漏表达）。我们报道了抑制核因子-κB（NF-κB）通过减少Ad基因在肝脏中的泄漏表达而导致抑制复制缺陷型Ad载体介导的肝毒性。在此，为了开发具有改善的安全性特征的TRAD，我们设计了携带肝脏特异性启动子驱动的显性负性IκBα（DNIκBα）表达盒（TRAD-DNIκ Bα）的TRAD。与传统TRAD相比，TRAD-DNIκBα能特异性抑制NF-κB信号通路，并显著降低正常人肝细胞系中Ad基因的表达和复制。TRAD-DNIκBα静脉给药后，小鼠中TRAD诱导的肝毒性在很大程度上受到抑制。然而，TRAD-DNIκBα在人非肝肿瘤细胞中的复制谱和溶瘤活性与常规TRAD相当。这些结果表明，含有肝特异性DNIκBα表达盒的溶瘤Ad具有改善的安全性，而不抑制溶瘤活性。
Telomerase-specific replication-competent adenoviruses (Ads), i.e., TRADs, which possess an E1 gene expression cassette driven by the human telomerase reverse transcriptase promoter, are promising agents for cancer treatment. However, even though oncolytic Ads, including TRAD, are intratumorally administered, they are disseminated from the tumor to systemic circulation, causing concern about oncolytic Ad-mediated hepatotoxicity (due mainly to leaky expression of Ad genes in liver). We reported that inhibition of nuclear factor-κB (NF-κB) leads to the suppression of replication-incompetent Ad vector-mediated hepatotoxicity via reduction of the leaky expression of Ad genes in liver. Here, to develop a TRAD with an improved safety profile, we designed a TRAD that carries a liver-specific promoter-driven dominant-negative IκBα (DNIκBα) expression cassette (TRAD-DNIκBα). Compared with a conventional TRAD, TRAD-DNIκBα showed hepatocyte-specific inhibition of NF-κB signaling and significantly reduced Ad gene expression and replication in the normal human hepatocyte cell line. TRAD-induced hepatotoxicity was largely suppressed in mice following intravenous administration of TRAD-DNIκBα. However, the replication profiles and oncolytic activities of TRAD-DNIκBα were comparable with those of the conventional TRAD in human non-hepatic tumor cells. These results indicate that oncolytic Ads containing the liver-specific DNIκBα expression cassette have improved safety profiles without inhibiting oncolytic activities.
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4.2
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