Abstract
Pancreatic cancer is an aggressive disease with limited therapeutic options. mda-7/IL-24, a potent anti-tumor cytokine, shows cancer-specific toxicity in a vast array of human cancers, inducing ER stress and apoptosis, toxic autophagy, an anti-tumor immune response, an anti-angiogenic effect and a significant ‘bystander’ anti-cancer effect that leads to enhanced production of this cytokine through autocrine and paracrine loops. Unfortunately, its applications in pancreatic cancer have been restricted due to a 'translational block' occurring after Ad.5-mda-7 gene delivery. Our previous research focused on developing approaches to overcome this block and increase the translation of the MDA-7/IL-24 protein thereby promoting its subsequent toxic effects in pancreatic cancer cells. We demonstrated that inducing reactive oxygen species (ROS) after adenoviral infection of mda-7/IL-24 leads to greater translation into MDA-7/IL-24 protein and results in toxicity in pancreatic cancer cells. In this study we demonstrate that a novel chimeric serotype adenovirus, Ad.5/3-mda-7, displays greater efficacy in delivering mda-7/IL-24 as compared to Ad.5-mda-7, although overall translation of the protein still remains low. We additionally show that D-Limonene, a dietary monoterpene known to induce ROS, is capable of overcoming the 'translational block' when used in combination with adenoviral gene delivery. This novel combination results in increased polysome association of mda-7/IL-24 mRNA, activation of the pre-initiation complex of the translational machinery in pancreatic cancer cells, and culminates in mda-7/IL-24-mediated toxicity.
- The American Society for Pharmacology and Experimental Therapeutics