Advantages of Using Paclitaxel in Combination with Oncolytic Adenovirus Utilizing RNA Destabilization Mechanism
Advantages of Using Paclitaxel in Combination with Oncolytic Adenovirus Utilizing RNA Destabilization Mechanism
复制标题
DOI：
10.3390/cancers12051210
复制
发表时间：
2020-05-01
期刊：
影响因子：
5.2
通讯作者：
Higashino, Fumihiro
中科院分区：
文献类型：
--
作者：
Hossain, Elora;Habiba, Umma;Higashino, Fumihiro
溶瘤病毒治疗是一种新型的肿瘤治疗方法。Ad-fosARE是一种条件复制型腺病毒，通过在E1 A基因的3 '非翻译区插入富含AU的元件（ARE）而设计。在这项研究中，我们检查了Ad-fosARE的溶瘤活性，并将其与化疗剂紫杉醇（PTX）协同组合用于治疗癌细胞。由于E1 A-ARE mRNA的稳定，E1 A在癌细胞中的表达较高。结果，其在癌细胞中的复制和细胞溶解活性的效率高于在正常细胞中。PTX治疗增加了癌细胞中的细胞质HuR重新定位，通过升高E1 A表达增强病毒复制，并上调病毒摄取所需的CAR（柯萨奇-腺病毒受体）。此外，PTX通过乙酰化和脱酪氨酸改变微管的不稳定性，这对于病毒内化和运输到细胞核是必不可少的。这些结果表明，PTX可以在体外和体内为Ad-fosARE的功效提供多种优势，并为设计新的临床试验提供了基础。因此，这种病毒具有许多在其他溶瘤病毒中没有发现的益处。这种病毒也有可能治疗对PXT耐药的癌症。
Oncolytic virotherapy is a novel approach to cancer therapy. Ad-fosARE is a conditionally replicative adenovirus engineered by inserting AU-rich elements (ARE) in the 3'-untranslated region of the E1A gene. In this study, we examined the oncolytic activity of Ad-fosARE and used it in a synergistic combination with the chemotherapeutic agent paclitaxel (PTX) for treating cancer cells. The expression of E1A was high in cancer cells due to stabilized E1A-ARE mRNA. As a result, the efficiency of its replication and cytolytic activity in cancer cells was higher than in normal cells. PTX treatment increased the cytoplasmic HuR relocalization in cancer cells, enhanced viral replication through elevated E1A expression, and upregulated CAR (Coxsackie-adenovirus receptor) required for viral uptake. Furthermore, PTX altered the instability of microtubules by acetylation and detyrosination, which is essential for viral internalization and trafficking to the nucleus. These results indicate that PTX can provide multiple advantages to the efficacy of Ad-fosARE both in vitro and in vivo, and provides a basis for designing novel clinical trials. Thus, this virus has a lot of benefits that are not found in other oncolytic viruses. The virus also has the potential for treating PXT-resistant cancers.