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J. Biol. Chem., Vol. 276, Issue 28, 25775-25782, July 13, 2001

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Tumoricidal Activity of Endothelial Cells
INHIBITION OF ENDOTHELIAL NITRIC OXIDE PRODUCTION ABROGATES TUMOR CYTOTOXICITY INDUCED BY HEPATIC SINUSOIDAL ENDOTHELIUM IN RESPONSE TO B16 MELANOMA ADHESION IN VITRO^*

Julian Carretero^§, Elena Obrador^¶, Juan M. Esteve, Angel Ortega, José A. Pellicer, Francisco Vera Sempere^**, and José M. Estrela

From the  Departamento de Fisiología, Universidad de Valencia, and the ^** Servicio de Anatomía Patológica, Hospital Universitario La Fe, Valencia, Spain

The mechanism of NO- and H₂O₂-induced tumor cytotoxicity was examined during B16 melanoma (B16M) adhesion to the hepatic sinusoidal endothelium (HSE) in vitro. We used endothelial nitric-oxide synthetase gene disruption and N^G-nitro-L-arginine methyl ester-induced inhibition of nitric-oxide synthetase activity to study the effect of HSE-derived NO on B16M cell viability. Extracellular H₂O₂ was removed by exogenous catalase. H₂O₂ was not cytotoxic in the absence of NO. However, NO-induced tumor cytotoxicity was increased by H₂O₂ due to the formation of potent oxidants, likely ^·OH and OONO radicals, via a trace metal-dependent process. B16M cells cultured to low density (LD cells), with high GSH content, were more resistant to NO and H₂O₂ than B16M cells cultured to high density (HD cells; with ~25% of the GSH content found in LD cells). Resistance of LD cells decreased using buthionine sulfoximine, a specific GSH synthesis inhibitor, whereas resistance increased in HD cells using GSH ester, which delivers free intracellular GSH. Because NO and H₂O₂ were particularly cytotoxic in HD cells, we investigated the enzyme activities that degrade H₂O₂. NO and H₂O₂ caused an ~75% (LD cells) and a 60% (HD cells) decrease in catalase activity without affecting the GSH peroxidase/GSH reductase system. Therefore, B16M resistance to the HSE-induced cytotoxicity appears highly dependent on GSH and GSH peroxidase, which are both required to eliminate H₂O₂. In agreement with this fact, ebselen, a GSH peroxidase mimic, abrogated the increase in NO toxicity induced by H₂O₂.

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