Tumoricidal activity of endothelium-derived NO and the survival of metastatic cells with high GSH and Bcl-2 levels.
Metastatic spread, not primary tumor burden, is the leading cause of cancer death. Glutathione (L-gamma-glutamyl-L-cysteinyl-glycine; GSH) is the most prevalent non-protein thiol in mammalian cells, and in cancer cells is particularly relevant in regulating mutagenic mechanisms, DNA synthesis, growth, and multidrug and radiation resistance. In malignant tumors, as compared with normal tissues, that resistance associates in most cases with higher GSH levels. Interaction of metastatic cells with the vascular endothelium activates local release of proinflammatory cytokines, which act as signals promoting cancer cell adhesion, extravasation, and proliferation. A high% of metastatic cells with high GSH levels survive the nitrosative and oxidative stresses elicited by the endothelium and possibly by macrophages and granulocytes. Gamma-glutamyl transpeptidase overexpression and an interorgan flow of GSH, by increasing cysteine availability for tumor GSH synthesis, promote metastatic growth. The mechanism of NO- and H(2)O(2)-induced tumor cytotoxicity has been examined during murine B16 melanoma (B16M) adhesion to the vascular endothelium. H(2)O(2) was not cytotoxic in the absence of NO. But, NO-induced tumor cytotoxicity was increased by H(2)O(2) due to the formation of potent oxidants, likely (.)OH and ((-))OONO radicals, via a trace metal-dependent process. B16M cells with high GSH content were more resistant to NO and H(2)O(2). Cancer cell survivors showed higher Bcl-2 and GSH levels. Metastatic invaders, after surviving attack by tissue macrophages, may further enhance their resistance.
Ortega
Angel
A
Department of Physiology, University of Valencia, 17 Av. Blasco Ibanez, Valencia 46010, Spain.
Carretero
Julian
J
Obrador
Elena
E
Estrela
José M
JM
D002470:Cell Survival; D004727:Endothelium / Q000378:metabolism; D005978:Glutathione / Q000032:analysis*; D006801:Humans; D009362:Neoplasm Metastasis / Q000473:pathology*; D009569:Nitric Oxide / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*
D019253:Proto-Oncogene Proteins c-bcl-2; D009569:Nitric Oxide; D005978:Glutathione