Gemcitabine combined with an engineered oncolytic vaccinia virus exhibits a synergistic suppressive effect on the tumor growth of pancreatic cancer

Abstract

Pancreatic cancer (PC) is a lethal solid malignancy with resistance to traditional chemotherapy. Recently, considerable studies have demonstrated the ubiquitous antitumor properties of gene therapy mediated by the oncolytic vaccinia virus. The second mitochondrial-derived activator of caspase (Smac) has been identified as an innovative tumor suppressor that augments the chemosensitivity of cancer cells. However, the therapeutic value of oncolytic vaccinia virus (oVV)-mediated Smac gene transfer in pancreatic cancer is yet to be elucidated. In the present study, oncolytic vaccinia virus expressing Smac (second mitochondrial-derived activator of caspase) (oVV-Smac) was used to examine its beneficial value when used alone or with gemcitabine in pancreatic cancer in vitro and in vivo. The expression of Smac was evaluated by western blot analysis and quantitative polymerase chain reaction, oVV-Smac cytotoxicity by MTT assay, and apoptosis by flow cytometry and western blot analysis. Furthermore, the inhibitory effect of oVV-Smac combined with gemcitabine was also evaluated. The results indicated that oVV-Smac achieved high levels of Smac, greater cytotoxicity, and potentiated apoptosis. Moreover, co-treatment with oVV-Smac and gemcitabine resulted in a synergistic effect in vitro and in vivo. Therefore, our findings advance oVV-Smac as a potential therapeutic candidate in pancreatic cancer and indicated the synergistic effects of co-treatment with oVV-Smac and gemcitabine.

Win or loss? Combination therapy does improve the oncolytic virus therapy to pancreatic cancer

“…The results showed Smac exhibited low expression in PC cell lines. Moreover, co‑treatment with oVV‑Smac and gemcitabine resulted in a synergistic effect [ 65 ]. Mechanically, oVV‑Smac replicates selectively in tumor cells, leading to their lysis, disrupting the tumor's protection and allowing gemcitabine to penetrate the PC tumor environment.…”

Expanding the Spectrum of Pancreatic Cancers Responsive to Vesicular Stomatitis Virus-Based Oncolytic Virotherapy: Challenges and Solutions

“…The addition of chemotherapies to OV therapy using a combination of an oncolytic herpes simplex virus-1 mutant NV1066 with 5-FU increased viral replication up to 19-fold compared with cells treated with virus alone, and similar results were achieved by the addition of gemcitabine [ 125 ]. Similarly, oVV-Smac combined with gemcitabine greater cytotoxicity and potentiated apoptosis [ 148 ]. H-1PV combined with cisplatin, vincristine or sunitinib induced effective immunostimulation via a pronounced DC maturation, better cytokine release and cytotoxic T-cell activation [ 154 ].…”

Combining Oncolytic Viruses and Small Molecule Therapeutics: Mutual Benefits

“…By interfering with DNA replication these antimetabolites induce inhibition of DNA synthesis with subsequent p53 upregulation, which ultimately can lead to cell death ( Figure 4 C) [ 162 ]. Naturally, these cytotoxic compounds combine well with several OVs [ 163 , 164 , 165 , 166 , 167 , 168 , 169 ]. However, these antimetabolites can also induce senescence of tumor cells which can regain proliferative activity after treatment cessation [ 170 ].…”