ABSTRACT
Effects of water-soluble phenolic antioxidant sodium 3-(3'-tret-butyl-4'-hydroxyphenyl)-propyl thiosulfonate (TS-13), potassium 3,5-dimethyl-4-hydroxybenzyl thioetanoate (BEP-11-K) and potassium 3-(3',5'-ditretbutyl-4'-hydroxyphenyl)-propionate (potassium phenosan) on tumor cells proliferative activity and the role of redox-dependent and calcium-dependent signaling mechanisms in realization of tumor cell response to the antioxidant action were studied. Potassium phenosan and BEP-11-K were found to stimulate proliferation and ARE-inducing phenolic antioxidant TS-13 was found to inhibit tumor cell growth in culture. The tumor cell growth rate depended on the rate of intracellular reactive oxygen species production and was decreased by apocynin (a NADPH-oxidase inhibitor) and antimycin A (an ubiquinol-cytochrome c oxidoreductase inhibitor). TS-13 action on tumor cells was accompanied by a transient increase in intracellular reactive oxygen species production and the intracellular calcium concentration, whereas cell incubation with potassium phenosan and BEP-11-K did not influence the reactive oxygen species level and intracellular calcium ions. Cyclosporine A blocked the inhibitory effect of TS-13. Thus, it can be reasonably speculated that phenolic antioxidant TS-13 starts mitochondria-dependent apoptosis in tumor cells by the opening of permeability transition pores.
Subject(s)
Antioxidants/pharmacology , Apoptosis/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Mitochondria/metabolism , Response Elements , Thiosulfonic Acids/pharmacology , Cell Line, Tumor , Humans , Mitochondria/pathology , NADPH Oxidases/antagonists & inhibitors , NADPH Oxidases/metabolism , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Neoplasms , Reactive Oxygen Species/metabolismABSTRACT
Transcription factor Nrf2 plays a key role in cell defense against oxidative stress, as well as in counteracting chemical and physical factors that induce apoptosis and carcinogenesis. The mechanism of Nrf2/ARE redox regulation and ARE-mediated gene expression are analyzed in the review. Special attention was paid to anti-inflammatory effects of Nrf2/ARE system, which significantly manifest in Nrf2 knockout animal.
Subject(s)
Gene Expression Regulation , Inflammation/metabolism , NF-E2-Related Factor 2/metabolism , Oxidative Stress , Signal Transduction , Animals , Apoptosis/genetics , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Humans , Inflammation/genetics , Mice , Mice, Knockout , NF-E2-Related Factor 2/geneticsABSTRACT
Unlike other cytochrome P450-dependent oxygenase inhibitors, ketoconazole has been shown to suppress the murine macrophage-mediated oxidative modification of human low-density lipoproteins (LDL) in a dose-dependent manner. The benzo[alpha]pyrene-induced microsomal monooxygenase activity was accomplished by a 1,5-fold increase in LDL oxidation by macrophages, ketokonazole (20 mu), methoxalene (20 mu), and alpha-naphthaflavone (50 mu). Ketoconazole was also effective in inhibiting macrophageal NADPH oxidase and LDL autooxidation induced by Fe2+ rather than Cu+, which is likely to be associated with its ability to act as a chelator of free and heme-bound iron ions.
Subject(s)
Cytochrome P-450 Enzyme Inhibitors , Enzyme Inhibitors/pharmacology , Lipoproteins, LDL/metabolism , Macrophages, Peritoneal/metabolism , Animals , Benzo(a)pyrene/pharmacology , Benzoflavones/pharmacology , Copper/pharmacology , Ferrous Compounds/pharmacology , Humans , Iron Chelating Agents/pharmacology , Ketoconazole/pharmacology , Luminescent Measurements , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/enzymology , Methoxsalen/pharmacology , Mice , NADPH Oxidases/antagonists & inhibitors , Oxidation-ReductionABSTRACT
Metabolic activity of peripheral blood granulocytes during the development of inflammatory processes in animals (rats) was studied by chemiluminescence (CL) with luminol. Intensification of the CL- response of granulocytes during an acute inflammatory process induced by intravenous or intraperitoneal zymosan injection reflected the development of mononuclear infiltrative processes. No changes occurred in CL of circulating granulocytes in oxidative injury to the lungs of rats breathing pure oxygen, which was attended by increased infiltration of polynuclear cells.
