Department of Hematology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, People's Republic of China.
Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, People's Republic of China.
Biomed Pharmacother. 2020 May;125:110030. doi: 10.1016/j.biopha.2020.110030. Epub 2020 Feb 27.
Different strategies were taken to make virotherapy more effective at killing cancer cells. Among them, oncolytic virus which arms the therapeutic gene to enhance antitumor activity is a prevalent approach. In this study, a newly developed oncolytic vaccinia virus (OVV) that expresses Beclin-1 (OVV-BECN1) was tested for its in vitro and in vivo oncolytic activity in blood cancer. Results showed that the OVV exhibited higher infectivity for leukemia cells. OVV-BECN1 induced significant apoptosis-independent cell death either in wild-type leukemia and multiple myeloma (MM) cell lines or caspase-3 shRNA leukemia cell lines, and had a superior antitumor activity compared to the parent OVV. Autophagic cell death induced by OVV-BECN1 was demonstrated in vitro and in vivo experiments. Finally, upregulation of SIRT-1, a member of class III histone deacetylases, by OVV-BECN1 resulted in the deacetylation of LC3 and its distribution from the nucleus toward the cytoplasm, which might contribute to induction of autophagy. Overall, our data showed a favorable therapeutic effect of the oncolytic vaccinia virus on blood cancers through oncolytic and autophagic mechanisms, and may therefore constitute a promising and effective therapeutic strategy for treating human leukemia and MM. However, further studies are warranted for its reliable clinical translation.
为了提高溶瘤病毒杀伤癌细胞的效果，人们采取了不同的策略。其中，携带治疗基因以增强抗肿瘤活性的溶瘤病毒是一种常见的方法。在这项研究中，我们测试了一种新开发的表达 Beclin-1 的溶瘤痘病毒（OVV-BECN1）在血液系统肿瘤中的体外和体内溶瘤活性。结果表明，该 OVV 对白血病细胞具有更高的感染力。OVV-BECN1 可诱导野生型白血病和多发性骨髓瘤（MM）细胞系或 caspase-3 shRNA 白血病细胞系发生明显的凋亡非依赖性细胞死亡，并且与亲本 OVV 相比具有更好的抗肿瘤活性。在体外和体内实验中证明了 OVV-BECN1 诱导的自噬性细胞死亡。最后，OVV-BECN1 上调了组蛋白去乙酰化酶 III 类中的 SIRT-1，导致 LC3 的去乙酰化及其从核内分布到细胞质中，这可能有助于诱导自噬。总的来说，我们的数据表明，溶瘤痘病毒通过溶瘤和自噬机制对血液系统肿瘤具有良好的治疗效果，因此可能成为治疗人类白血病和 MM 的一种有前途且有效的治疗策略。然而，仍需要进一步的研究来保证其可靠的临床转化。
