Document Detail

Targeting hepatoma using nitric oxide donor strategies.
MedLine Citation:
PMID:  22861189     Owner:  NLM     Status:  MEDLINE    
AIMS: The study evaluated the role of increased intracellular nitric oxide (NO) concentration using NO donors or stably NO synthase-3 (NOS-3) overexpression during CD95-dependent cell death in hepatoma cells. The expression of cell death receptors and caspase activation, RhoA kinase activity, NOS-3 expression/activity, oxidative/nitrosative stress, and p53 expression were analyzed. The antitumoral activity of NO was also evaluated in the subcutaneous implantation of NOS-3-overexpressing hepatoma cells, as well NO donor injection into wild-type hepatoma-derived tumors implanted in xenograft mouse models.
RESULTS: NO donor increased CD95 expression and activation of caspase-8 and 3 in HepG2, Huh7, and Hep3B cells. NOS-3 overexpression increased oxidative/nitrosative stress, p53 and CD95 expression, cellular Fas-associated death domain (FADD)-like IL-1beta converting enzyme (FLICE) inhibitory protein long (cFLIP(L)) and its short isoform (cFLIP(S)) shift, and cell death in HepG2 (4TO-NOS) cells. The inhibition of RhoA kinase and p53 knockdown using RNA interference reduced cell death in 4TO-NOS cells. The supplementation with hydrogen peroxide (H(2)O(2)) increased NOS-3 activity and cell death in 4TO-NOS cells. NOS-3 overexpression or NO donor injection into hepatoma-derived tumors reduced the size and increased p53 and cell death receptor expression in nude mice.
INNOVATION AND CONCLUSIONS: The increase of intracellular NO concentration promoted oxidative and nitrosative stress, Rho kinase activity, p53 and CD95 expression, and cell death in cultured hepatoma cells. NOS-3-overexpressed HepG2 cells or intratumoral NO donor administration reduced tumor cell growth and increased the expression of p53 and cell death receptors in tumors developed in a xenograft mouse model.
Raúl González; Gustavo Ferrín; Patricia Aguilar-Melero; Isidora Ranchal; Clara I Linares; Rosario I Bello; Manuel De la Mata; Vladimir Gogvadze; José A Bárcena; José M Alamo; Sten Orrenius; Francisco J Padillo; Boris Zhivotovsky; Jordi Muntané
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-09-26
Journal Detail:
Title:  Antioxidants & redox signaling     Volume:  18     ISSN:  1557-7716     ISO Abbreviation:  Antioxid. Redox Signal.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-10     Completed Date:  2013-06-07     Revised Date:  2014-11-13    
Medline Journal Info:
Nlm Unique ID:  100888899     Medline TA:  Antioxid Redox Signal     Country:  United States    
Other Details:
Languages:  eng     Pagination:  491-506     Citation Subset:  IM    
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MeSH Terms
Antigens, CD95 / metabolism
Carcinoma, Hepatocellular / enzymology,  metabolism*,  pathology
Cell Line, Tumor
Genes, p53
Liver Neoplasms / enzymology,  metabolism*,  pathology
Nitric Oxide Donors / pharmacology*
Xenograft Model Antitumor Assays
rhoA GTP-Binding Protein / metabolism
Reg. No./Substance:
0/Antigens, CD95; 0/Nitric Oxide Donors; 124671-05-2/RHOA protein, human; EC GTP-Binding Protein

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