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

摘要: The mechanism of NO- and H(2)O(2)-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 N(G)-nitro-l-arginine methyl ester-induced inhibition activity study effect HSE-derived NO on B16M cell viability. Extracellular H(2)O(2) removed by exogenous catalase. not cytotoxic absence NO. However, NO-induced increased due formation potent oxidants, likely ( small middle dot)OH (-)OONO radicals, via a trace metal-dependent process. cells cultured low density (LD cells), with high GSH content, were more resistant than (HD cells; approximately 25% content found LD cells). Resistance decreased using buthionine sulfoximine, specific synthesis inhibitor, whereas resistance HD ester, which delivers free intracellular GSH. Because particularly cells, we investigated enzyme activities that degrade H(2)O(2). caused an 75% cells) 60% decrease catalase without affecting peroxidase/GSH reductase system. Therefore, HSE-induced appears highly dependent peroxidase, are both required eliminate In agreement this fact, ebselen, peroxidase mimic, abrogated increase toxicity induced