Targeting eNOS in pancreatic cancer

Benjamin L. Lampson, S. Di Sean Kendall, Brooke B. Ancrile, Meghan M. Morrison, Michael J. Shealy, Katharine S. Barrientos, Matthew S. Crowe, David F. Kashatus, Rebekah R. White, Susan B. Gurley, Diana M. Cardona, Christopher M. Counter

Research output: Contribution to journalArticle

32 Scopus citations

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 NG-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.

Original languageEnglish (US)
Pages (from-to)4472-4482
Number of pages11
JournalCancer Research
Volume72
Issue number17
DOIs
StatePublished - Sep 1 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Lampson, B. L., Kendall, S. D. S., Ancrile, B. B., Morrison, M. M., Shealy, M. J., Barrientos, K. S., Crowe, M. S., Kashatus, D. F., White, R. R., Gurley, S. B., Cardona, D. M., & Counter, C. M. (2012). Targeting eNOS in pancreatic cancer. Cancer Research, 72(17), 4472-4482. https://doi.org/10.1158/0008-5472.CAN-12-0057