Combined expression of miR-34a and Smac mediated by oncolytic vaccinia virus synergistically promote anti-tumor effects in Multiple Myeloma

Abstract

Despite great progress made in the treatment of multiple myeloma (MM), it is still incurable. Promising phase II clinical results have been reported recently for oncolytic vaccinia virus (OVV) clinic therapeutics. One reason for this has focused on the critical therapeutic importance of the immune response raised by these viruses. However, few studies have performed their applications as an optimal delivery system for therapeutic gene, especially miRNA in MM. In this study, we constructed two novel OVVs (TK deletion) that express anti-tumor genes, miR-34a and Smac, respectively, in MM cell lines and xenograft model. The results demonstrated that the novel OVV can effectively infect MM cell lines, and forcefully enhance the exogenous gene (miR-34a or Smac) expression. Furthermore, utilization of VV-miR-34a combined with VV-Smac synergistically inhibited tumor growth and induced apoptosis in vitro and in vivo. The underlying mechanism is proposed that blocking of Bcl-2 by VV-miR-34a increases the release of cytochrome c from mitochondria and then synergistically amplifies the antitumor effects of Smac-induced cell apoptosis. Our study is the first to utilize OVV as the vector for miR-34a or Smac expression to treat MM, and lays the groundwork for future clinical therapy for MM.

Gambogenic Acid Exerts Antitumor Activity in Hypoxic Multiple Myeloma Cells by Regulation of miR-21

“…MM represents the second most frequent hematologic disease with an annual incidence of 6.3 new cases per 100,000 individuals 19 . It remains incurable in many cases despite the variety of therapies already introduced, thus illustrating in-depth study of its pathogenesis and the urgent need for innovative therapeutic methods 20 - 22 . Traditional Chinese medicines have proven to be an attractive option for treatment of tumors due to their tumor suppressive activity.…”

miR‐215‐5p is an anticancer gene in multiple myeloma by targeting RUNX1 and deactivating the PI3K/AKT/mTOR pathway

“…Particularly, microRNAs (miRNAs) have attracted great attention as markers for tumor diagnosis. 1,[4][5][6] miRNAs, endogenous noncoding miRNAs 18 to 23 bases in length, are evolutionally conserved. According to reports, miRNAs play certain roles in the pathogenesis, occurrence, as well as the development of cancer.…”

Immunotherapy in Multiple Myeloma

“…The vaccinia virus has shown promising results in the treatment of solid tumors but data in hematologic malignancies is less robust [177]. In MM, the evidence for vaccinia as an OV agent are conflicting, with some studies showing potent lytic activity while others showing only modest reductions in cell viability [196,197]. Given the historical data supporting the use of this virus as a base for vaccines, ongoing studies are aiming to establish whether vaccinia can be used to generate anti-myeloma vaccines [177].…”