Enhancing therapeutic efficacy of oncolytic vaccinia virus armed with Beclin-1, an autophagic Gene in leukemia and myeloma

• Published in: Biomedicine & pharmacotherapy Vol. 125; p. 110030
• Main Authors: Lei, Wen, Wang, Shibing, Xu, Nengwen, Chen, Yu, Wu, Gongqiang, Zhang, Aibin, Chen, Xiaomin, Tong, Yin, Qian, Wenbin
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.05.2020; Elsevier
• Subjects: Animals; Apoptosis - physiology; Autophagic cell death; Autophagy - genetics; Beclin-1; Beclin-1 - genetics; Blood cancers; Cell Line, Tumor; Humans; Leukemia - pathology; Leukemia - therapy; Mice; Mice, Inbred NOD; Mice, SCID; Multiple Myeloma - pathology; Multiple Myeloma - therapy; Oncolytic vaccinia virus; Oncolytic Virotherapy - methods; Oncolytic Viruses - genetics; SIRT-1; Vaccinia virus - genetics; Xenograft Model Antitumor Assays; Beclin-1; Oncolytic vaccinia virus; Autophagic cell death; SIRT-1; Blood cancers
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2020.110030

•Oncolytic virus armed therapeutic genes enhanced the antitumor activity in blood cancer.•OVV-BECN1 induced the autophagic cell death in apoptosis resistant tumoral cells.•Upregulation of SIRT-1 and deacetylation of LC3 is the underlying mechanism.•Deacetylation of LC3 results in its transformation from nucleus to cytoplasm. 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.