@article {Sarkarmol.114.094375, author = {Siddik Sarkar and Bridget A Quinn and Xuening Shen and Paul Dent and Swadesh Das and Luni Emdad and Devanand Sarkar and Paul B Fisher}, title = {Reversing Translational Suppression and Induction of Toxicity in Pancreatic Cancer Cells Using a Chemoprevention Gene Therapy (CGT) Approach}, elocation-id = {mol.114.094375}, year = {2014}, doi = {10.1124/mol.114.094375}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, 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 {\textquoteleft}bystander{\textquoteright} 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 {\textquoteright}translational block{\textquoteright} 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 {\textquoteright}translational block{\textquoteright} 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.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/early/2014/12/01/mol.114.094375}, eprint = {https://molpharm.aspetjournals.org/content/early/2014/12/01/mol.114.094375.full.pdf}, journal = {Molecular Pharmacology} }