Pancreatic cancer-specific cell death induced in vivo by cytoplasmic-delivered polyinosine-polycytidylic acid
- Authors: Bhoopathi, P., Quinn, B. A., Gui, Q., Shen, X. N., Grossman, S. R., Das, S. K., Sarkar, D., Fisher, P. B., Emdad, L.
- Year: 2014
- Journal: Cancer Res 74 6224-35
- Applications: in vivo / Poly (I:C) / in vivo-jetPEI
1mg/kg of poly(I:C) complexed with in vivo-jetPEI was injected peritumorally for pancreatic xenografts (MIA PaCa-2 cells injected subcutaneously) or intraperitoneally for quasi-orthotopic tumors (MIA PaCa-2 cells injected intraperitoneally). Injections were repeated 4 times, twice weekly for 2 weeks and led to 90% tumor growth inhibition.
Polyinosine-polycytidylic acid [pIC] is a synthetic dsRNA that acts as an immune agonist of TLR3 and RLR to activate dendritic and natural killer cells that can kill tumor cells. pIC can also trigger apoptosis in pancreatic ductal adenocarcinoma cells (PDAC) but its mechanism of action is obscure. In this study, we investigated the potential therapeutic activity of a formulation of pIC with polyethylenimine ([pIC](PEI)) in PDAC and investigated its mechanism of action. [pIC](PEI) stimulated apoptosis in PDAC cells without affecting normal pancreatic epithelial cells. Mechanistically, [pIC](PEI) repressed XIAP and survivin expression and activated an immune response by inducing MDA-5, RIG-I, and NOXA. Phosphorylation of AKT was inhibited by [pIC](PEI) in PDAC, and this event was critical for stimulating apoptosis through XIAP and survivin degradation. In vivo administration of [pIC](PEI) inhibited tumor growth via AKT-mediated XIAP degradation in both subcutaneous and quasi-orthotopic models of PDAC. Taken together, these results offer a preclinical proof-of-concept for the evaluation of [pIC](PEI) as an immunochemotherapy to treat pancreatic cancer.