Targeting eNOS in pancreatic cancer.
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.
Departments of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
Benjamin L
BL
Lampson
S Disean
SD
Kendall
Brooke B
BB
Ancrile
Meghan M
MM
Morrison
Michael J
MJ
Shealy
Katharine S
KS
Barrientos
Matthew S
MS
Crowe
David F
DF
Kashatus
Rebekah R
RR
White
Susan B
SB
Gurley
Diana M
DM
Cardona
Christopher M
CM
Counter
D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000401:mortality; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000401:mortality; D017154:Stromal Cells / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D000959:Antihypertensive Agents; D000970:Antineoplastic Agents; D052250:Nitric Oxide Synthase Type III; D018631:ras Proteins; D019331:NG-Nitroarginine Methyl Ester