ABSTRACT
Fatty acid hydroperoxides are produced from unsaturated fatty acids in the presence of oxygen at elevated temperatures during food processing. Their effects on gene expression in colorectal tumour cells were studied using linoleic acid hydroperoxide (LOOH) as a model compound. Addition of LOOH to the medium of LT97 adenoma and SW480 carcinoma cells enhanced the production of hydrogen peroxide. Both cell lines were observed to increase VEGF factors based on mRNA. High consumption of dietary fat promotes colon carcinogenesis in the long-term. While this effect is well known, the underlying mechanisms are not understood. An approach was made starting from the assumption that LOOH is present in dietary fats as a result of heating. LOOH undergoes homolytic cleavage in the presence of iron. Various radicals are formed on mixing LT97 or SW480 cells with LOOH. The expression of tumour-promoting factors was inhibited by caroverine and ubiquinone, which may be justified as active chemopreventive agents.
Subject(s)
Anticarcinogenic Agents/pharmacology , Colonic Neoplasms/prevention & control , Linoleic Acids/antagonists & inhibitors , Lipid Peroxides/antagonists & inhibitors , Quinoxalines/pharmacology , Ubiquinone/pharmacology , Adenoma/genetics , Adenoma/metabolism , Antioxidants/pharmacology , Carcinoma/genetics , Carcinoma/metabolism , Cell Line, Tumor , Colonic Neoplasms/etiology , Colonic Neoplasms/genetics , Colonic Neoplasms/metabolism , Dietary Fats/adverse effects , Dietary Fats/metabolism , Gene Expression/drug effects , Humans , Hydrogen Peroxide/metabolism , Hydroxyl Radical/metabolism , Linoleic Acid/administration & dosage , Linoleic Acid/metabolism , Linoleic Acids/administration & dosage , Linoleic Acids/metabolism , Linoleic Acids/toxicity , Lipid Peroxides/administration & dosage , Lipid Peroxides/metabolism , Lipid Peroxides/toxicity , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/biosynthesis , Vascular Endothelial Growth Factor A/geneticsABSTRACT
High consumption of dietary fat promotes colon carcinogenesis. While this effect is well known the underlying mechanism is not understood. Fatty acid hydroperoxides (LOOH) arise from unsaturated fatty acids in the presence of oxygen and elevated temperature during food processing. An approach was made starting from the assumption that LOOH are present in dietary fats as a result of boiling. LOOH undergoes homolytic cleavage in the presence of iron. We studied their effects on gene expression in colorectal tumour cells using linoleic acid hydroperoxide (LOOH) as model compound. Addition to the medium of LT97 adenoma and SW480 carcinoma cells enhanced the production of hydrogen peroxide. Both cell lines were observed to increase VEGF and COX-II expression based on mRNA. Expression of VEGF was inhibited by caroverine and ubiquinon.
Subject(s)
Dietary Fats/adverse effects , Gene Expression Regulation, Neoplastic/drug effects , Linoleic Acids/pharmacology , Lipid Peroxides/pharmacology , Quinoxalines/pharmacology , Ubiquinone/analogs & derivatives , Adenoma , Carcinoma , Colonic Neoplasms , Cyclooxygenase 1/biosynthesis , Cyclooxygenase 2/biosynthesis , Cyclooxygenase Inhibitors/pharmacology , Humans , Organic Chemicals/pharmacology , Pyrazoles/pharmacology , Sulfonamides/pharmacology , Tumor Cells, Cultured/drug effects , Ubiquinone/pharmacology , Vascular Endothelial Growth Factor A/biosynthesisABSTRACT
Caroverine, 1-(2-diethylaminoethyl)-3-(p-methoxy benzyl)-1,2-dihydro-2-quinoxalin-2-on-hydrochloride, is a class B calcium-channel-blocker and antiglutamatergic agent with significant effects on the brain function. Caroverine exhibits competitive AMPA antagonism, and at higher concentrations, noncompetitive NMDA antagonism. In clinical practice caroverine is used as a spasmolytic and otoneuroprotective agent. Since reactive oxygen species are supposed to be involved in the pathogenesis of inner ear diseases in which caroverine shows beneficial effects, the present study aimed to investigate the antioxidant properties of caroverine. Lipid peroxidation of liposomal membranes was suppressed in the presence of caroverine. In order to understand the mechanism of this antioxidant action of caroverine, we determined the rate constants both for a possible reaction with superoxide (O(2)(.-)) radicals from xanthine/xanthine oxidase and for a possible reaction with hydroxyl (.OH) radicals in Fenton system. Using a defined chemical reaction model O(2)(.-) scavenging was found to occur at a rather low rate constant only (3 x 10(2)M(-1)s(-1)). Thus, a reaction of caroverine with O(2)(.-) radicals is of marginal significance. In contrast, the reaction of caroverine with .OH radicals occurs at an extremely high rate constant (k=1.9 x 10(10)M(-1)s(-1)). The strong antioxidant activity of caroverine is therefore based both on the partial prevention and highly active scavenging of hydroxyl radicals.
Subject(s)
Antioxidants/pharmacology , Lipid Peroxidation/drug effects , Quinoxalines/pharmacology , Analysis of Variance , Calcium Channel Blockers/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Hydroxyl Radical/metabolism , Superoxides/metabolism , Vitamin E/metabolismABSTRACT
Here we show that lipid peroxidation of liposomal membranes was suppressed in the presence of Caroverine, a spasmolytic drug used in some countries. In order to understand the mechanism of this antioxidant action of Caroverine we studied the interaction of Caroverine with superoxide radicals, hydroxyl radicals and peroxynitrite. The results of the study show that the reaction of Caroverine with O2-* radicals is of marginal significance. However, it is efficient in removing peroxynitrite and a particular high reaction constant was found for reaction with hydroxyl radicals. The strong antioxidant activity of Caroverine is therefore based both on the partial prevention of the formation and the highly active scavenging of hydroxyl radicals.
