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Targeting nitric oxide (NO) signaling with nNOS inhibitors as a novel strategy for the therapy and prevention of human melanoma.
MedLine Citation:
PMID:  23199242     Owner:  NLM     Status:  Publisher    
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 are to determine the role of nNOS in melanoma progression and the potential anti-tumor effects of novel synthesized nNOS inhibitors. Results: In vitro studies demonstrated abundant expression of nNOS in melanoma compared to melanocytes, which was inducible by UV 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 was 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 3-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 over-production of NO, which stimulates proliferation and, increases invasion potential, leading to subsequent development of metastases.
Authors:
Sun Yang; Zhen Yang; Haitao Ji; Tom Poulos; Richard B Silverman; Bobbye Misner; Frank L Meyskens
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-12-2
Journal Detail:
Title:  Antioxidants & redox signaling     Volume:  -     ISSN:  1557-7716     ISO Abbreviation:  Antioxid. Redox Signal.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-3     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100888899     Medline TA:  Antioxid Redox Signal     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Chao Family Comprehensive Cancer Center, Medicine, 101 The City Drive S, Bldg 23, Rm 436B, Orange, California, United States, 92868, 714-456-3438, 714-456-2240; syang2@uci.edu.
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