title: Targeting nitric oxide signaling with nNOS inhibitors as a novel strategy for the therapy and prevention of human melanoma.
abstract: OBJECTIVE
  Our previous studies have shown that nitric oxide (NO) plays an important role in increasing the invasion and proliferation of human melanoma cells, suggesting that targeting NO signaling may facilitate therapy and prevention. Neuronal nitric oxide synthase (nNOS) is present in melanocytes, a cell type that originates from the neural crest. The aims of this study were to determine the role of nNOS in melanoma progression and the potential antitumor effects of novel synthesized nNOS inhibitors.
  
  
  RESULTS
  In vitro studies demonstrated abundant expression of nNOS in melanoma compared to melanocytes, which was inducible by ultraviolet radiation and was associated with increased NO generation. nNOS was also detected in melanoma biopsies that increased with disease stage. Knockdown of nNOS in melanoma cells diminished L-arginine-induced NO production; the metastatic capacity was also reduced as well as the levels of MMP-1, Bcl-2, JunD, and APE/Ref-1. Similar inhibition of NO and invasion potential was observed utilizing novel, highly selective nNOS inhibitors. In three-dimensional human skin reconstructs, the nNOS inhibitor cpd8 effectively reversed the melanoma overgrowth stimulated by NO stress.
  
  
  METHODS
  Our work lays the foundation for development of clinical "drug-like" nNOS inhibitors as a new and promising strategy for the chemoprevention of early melanoma progression and the inhibition of secondary melanoma in high-risk individuals.
  
  
  CONCLUSIONS
  Based on our observations, we propose that nNOS in melanoma results in constitutive overproduction of NO, which stimulates proliferation and increases invasion potential, leading to subsequent development of metastases.
authors.affiliation: Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, California, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yang
authors.forename: Bobbye
authors.initials: B
authors.lastname: Misner
authors.forename: Haitao
authors.initials: H
authors.lastname: Ji
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Poulos
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
authors.forename: Frank L
authors.initials: FL
authors.lastname: Meyskens
authors.forename: Sun
authors.initials: S
authors.lastname: Yang
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000187:drug effects / Q000201:enzymology / Q000528:radiation effects; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology*; D051379:Mice; D008819:Mice, Nude; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
chemical_list: D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D009569:Nitric Oxide; D001120:Arginine; D052248:Nitric Oxide Synthase Type I