1. Targeting eNOS in pancreatic cancer.
- Author
-
Lampson BL, Kendall SD, Ancrile BB, Morrison MM, Shealy MJ, Barrientos KS, Crowe MS, Kashatus DF, White RR, Gurley SB, Cardona DM, and Counter CM
- Subjects
- Animals, Antihypertensive Agents administration & dosage, Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacology, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal mortality, Cell Line, Tumor, Cell Transformation, Neoplastic genetics, Gene Expression Regulation, Neoplastic, Humans, Mice, Mice, Transgenic, NG-Nitroarginine Methyl Ester administration & dosage, NG-Nitroarginine Methyl Ester pharmacology, Nitric Oxide Synthase Type III antagonists & inhibitors, Nitric Oxide Synthase Type III genetics, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms genetics, Pancreatic Neoplasms mortality, Stromal Cells metabolism, Tumor Burden drug effects, Xenograft Model Antitumor Assays, ras Proteins genetics, ras Proteins metabolism, Carcinoma, Pancreatic Ductal enzymology, Nitric Oxide Synthase Type III metabolism, Pancreatic Neoplasms enzymology
- Abstract
Mortality from pancreatic ductal adenocarcinoma cancer (PDAC) is among the highest of any cancer and frontline therapy has changed little in years. Activation of endothelial nitric oxide synthase (eNOS, NOS3, or NOS III) has been implicated recently in the pathogenesis of PDACs. In this study, we used genetically engineered mouse and human xenograft models to evaluate the consequences of targeting eNOS in PDACs. Genetic deficiency in eNOS limited the development of preinvasive pancreatic lesions and trended toward an extended lifespan in mice with advanced pancreatic cancer. These effects were also observed upon oral administration of the clinically evaluated NOS small molecule inhibitor N(G)-nitro-L-arginine methyl ester (l-NAME). Similarly, other transgenic models of oncogenic KRas-driven tumors responded to l-NAME treatment. Finally, these results were recapitulated in xenograft models of human pancreatic cancer, in which l-NAME was found to broadly inhibit tumorigenic growth. Taken together, our findings offer preclinical proof-of-principle to repurpose l-NAME for clinical investigations in treatment of PDACs and possibly other KRas-driven human cancers., (©2012 AACR.)
- Published
- 2012
- Full Text
- View/download PDF