Dual silencing of Bcl-2 and Survivin by HSV-1 vector shows better antitumor efficacy in higher PKR phosphorylation tumor cells in vitro and in vivo

Abstract

RNA interference (RNAi) is a promising tool for cancer therapy, but its delivery strategy is a major challenge for its application. Oncolytic herpes simplex virus type 1 (HSV-1) is not only an effective antitumor drug but also an excellent vector. Herein, RNAi of oncogenes Bcl-2 and Survivin was combined with oncolytic HSV-1 (ICP34.5-/ICP6-/ICP47-/CMV-GM-CSF) and a new vector HSV010-BS was constructed. Transfected cell viability assays and animal experiments revealed that the dual silencing of Bcl-2 and Survivin improved the antitumor effect of oncolytic HSV-1 in vitro and in vivo, while the antitumor effect was correlated with the phosphorylation levels of PKR of the tumor cells. The higher the phosphorylation levels of PKR of the tumor cells, the weaker the replication ability of oncolytic HSV-1, and the more powerful HSV010-BS was than its control vectors in inhibiting the growth of the tumor cells. The results provided direct supportive proofs for a new potential cancer therapy strategy.

Co-transfection of decorin and interleukin-10 modulates pro-fibrotic extracellular matrix gene expression in human tenocyte culture

“…Hence, we believe that simultaneous delivery of pDCN+IL-10 modulates the opposing functions of DCN, leading to lower elastin gene expression at transcriptional level. These observations, not only illustrate the independent mode of action of the plasmids, but also corroborate previous publications, where co-delivery of therapeutics/biologics was demonstrated to be superior to mono-domain approaches 62 63 64 65 66 67 .…”

ErbB3-Targeting Oncolytic Adenovirus Causes Potent Tumor Suppression by Induction of Apoptosis in Cancer Cells

“…Furthermore, by in vitro and in vivo assays, we found that the replication-competent oncolytic adenovirus caused E1A-mediated simultaneous downregulation for ErbB2 and ErbB3 proteins, accounting for its enhanced potency. Chen et al [65] and Chang et al [66] have reported that E1A causes downregulation of HSPA5 and HER2/neu expression and is positively associated with tumor metastasis. Taken together with these reports, oAd/shErbB3-mediated ErbB3 downregulation is predicted to cause multimodal anticancer effects, and it could be an interesting combination therapy candidate for ErbB2-targeted therapies to address the ErbB2/ErbB3 heterodimerization-induced drug resistance in the future.…”

“…Mortalin-targeting oncolytic adenovirus was also shown to cause apoptosis in MCF7 cells [67]. Dual silencing of Bcl-2 and survivin by an oHSV-1 vector demonstrates antitumor efficacy in cancer cells [65]. Further, there are trials focusing on developing and establishing this platform more effectively by optimizing the structure and format of RNAi [66,68].…”

Oncolytic Engineering of ICP34.5 and LAT of Herpes Simplex Virus Type 1

“…During HSV infection (Figure 1), the host cells bind type I IFN through the IFN receptor, activate the JAK-STAT pathway and upregulate protein kinase R (PKR). Then PKR is activated by its ligand, which will cause phosphorylation of the host's translation initiation factor eIF2α, thereby inhibiting HSV replication and host protein synthesis [17]. However, the C-terminal domain of HSV ICP34.5 protein can bind to host phosphatase PP1α and relocate it to eIF2α, leading to dephosphorylation and restoration of mRNA translation [18] [19].…”