Document Detail


Targeting nitric oxide signaling with nNOS inhibitors as a novel strategy for the therapy and prevention of human melanoma.
MedLine Citation:
PMID:  23199242     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AIMS: 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.
INNOVATION: 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.
CONCLUSION: 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:
Zhen Yang; Bobbye Misner; Haitao Ji; Thomas L Poulos; Richard B Silverman; Frank L Meyskens; Sun Yang
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-01-18
Journal Detail:
Title:  Antioxidants & redox signaling     Volume:  19     ISSN:  1557-7716     ISO Abbreviation:  Antioxid. Redox Signal.     Publication Date:  2013 Aug 
Date Detail:
Created Date:  2013-07-09     Completed Date:  2014-01-31     Revised Date:  2014-08-12    
Medline Journal Info:
Nlm Unique ID:  100888899     Medline TA:  Antioxid Redox Signal     Country:  United States    
Other Details:
Languages:  eng     Pagination:  433-47     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Arginine / pharmacology*
Blotting, Western
Cell Line
Cells, Cultured
Enzyme Inhibitors / therapeutic use*
Humans
Male
Melanocytes / drug effects,  enzymology,  radiation effects
Melanoma / drug therapy*,  enzymology*
Mice
Mice, Nude
Nitric Oxide / metabolism*
Nitric Oxide Synthase Type I / antagonists & inhibitors*,  genetics,  metabolism*
RNA, Small Interfering
Tumor Cells, Cultured
Ultraviolet Rays
Grant Support
ID/Acronym/Agency:
GM49725/GM/NIGMS NIH HHS; GM57353/GM/NIGMS NIH HHS; R01 GM049725/GM/NIGMS NIH HHS; R01 GM057353/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/RNA, Small Interfering; 31C4KY9ESH/Nitric Oxide; 94ZLA3W45F/Arginine; EC 1.14.13.39/Nitric Oxide Synthase Type I
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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