Targeting eNOS in pancreatic cancer.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Lampson, BL; Kendall, SD; Ancrile, BB; Morrison, MM; Shealy, MJ; Barrientos, KS; Crowe, MS; Kashatus, DF; White, RR; Gurley, SB; Cardona, DM; Counter, CM

Published Date

  • September 1, 2012

Published In

Volume / Issue

  • 72 / 17

Start / End Page

  • 4472 - 4482

PubMed ID

  • 22738914

Pubmed Central ID

  • PMC3749841

Electronic International Standard Serial Number (EISSN)

  • 1538-7445

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-12-0057


  • eng

Conference Location

  • United States