Abstract
With no effective treatments available for most pancreatic cancer patients, pancreatic cancer continues to be one of the most difficult malignancies to treat. Oncolytic virus mediated-gene therapy has exhibited ubiquitous antitumor potential. In this study, we constructed a novel oncolytic vaccinia virus harboring the inhibitor of growth family member 4 gene (VV-ING4) to investigate its therapeutic efficacy alone or in combination with gemcitabine against pancreatic cancer cells in vitro and in vivo. ING4 expression was determined via quantitative real-time polymerase chain reaction (qPCR) and western blot. The cytotoxicity of VV-ING4 was measured using a cell proliferation assay. Both flow cytometry and western blot were applied to analyze the cell cycle and apoptosis. Furthermore, the combination inhibitory effect of VV-ING4 and gemcitabine was assessed using Chou-Talalay analysis in vitro and a BLAB/c mice model in vivo. We found that VV-ING4 significantly increases ING4 expression, displayed greater cytotoxic efficiency, and induced pancreatic cancer cell apoptosis and G2/M phase arrest. Additionally, the combination of VV-ING4 and gemcitabine synergistically effect in vitro and in vivo. Taken together, our data implicate VV-ING4 as a conceivable pancreatic cancer therapeutic candidate alone or in combination with gemcitabine.
Highlights
Pancreatic cancer is an extremely lethal disease
We found that oncolytic vaccinia virus (VV)-inhibitor of growth family member 4 (ING4) significantly increases ING4 expression, displayed greater cytotoxic efficiency, and induced pancreatic cancer cell apoptosis and G2/M phase arrest
We constructed an expression cassette consisting of the ING4 gene and the gpt selection gene promoted by the viral promoter Pse/L or P7.5k, respectively
Summary
Pancreatic cancer is an extremely lethal disease. It is the fourth most prevalent cause of cancer death, with a 5-year survival rate of only 5% [1, 2]. Complete surgical abscission remains the only curative treatment. Only 10% to 20% of pancreatic tumors are in a position in which they can be surgically removed at the time of diagnosis [3]. For patients with unresectable or metastatic pancreatic tumors, chemotherapy with gemcitabine (Gem) is the firstline therapy. Acquired resistance to gemcitabine has become an increasing challenge in treating pancreatic tumors [4]. More potent treatments are needed to improve the outcome of patients with pancreatic cancer
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