title: Involvement of oxidative DNA damage and apoptosis in antitumor actions of aminosugars.
abstract: We investigated the mechanisms of apoptosis and DNA damage induced by aminosugars in relation to their antitumor actions. The order of cytotoxic effects of aminosugars was D-mannosamine (ManN) >> D-galactosamine (GalN) > D-glucosamine (GlcN). A comparison of the frequency of apoptotic cells showed the same order. DNA ladders were formed by only ManN and the formation of DNA ladders was inhibited by a caspase inhibitor. Pulsed-field gel electrophoresis showed that ManN caused cellular DNA cleavage at a lower concentration than those causing apoptosis. Cellular DNA cleavage was inhibited by catalase and enhanced by a catalase inhibitor. Flow cytometry showed that ManN enhanced the production of intracellular peroxides. These results suggest that ManN-induced apoptosis is preceded by H2O2-mediated DNA damage. The order of the extent of damage to 32P-labeled DNA fragments by aminosugars plus Cu(II) was ManN >> GalN > GlcN. The DNA damage was inhibited by catalase and bathocuproine, suggesting that H2O2 reacts with Cu(I) to form the metal-peroxide complex capable of causing DNA damage. Two mechanisms of H2O2 generation from aminosugars were proposed: one is the major pathway to form a dioxo compound and NH4+; the other is the minor pathway to form a pyrazine derivative through the condensation of two molecules of an aminosugar. The order of reactivity to generate these products was ManN >> GalN > GlcN. On the basis of these results, it is concluded that aminosugars, especially ManN, produce H2O2 to cause DNA damage, which mediates apoptosis resulting in tumor growth inhibition.
authors.affiliation: Department of Hygiene, Mie University School of Medicine, Tsu, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hiraku
authors.forename: S
authors.initials: S
authors.lastname: Kawanishi
mesh_terms: D000606:Amino Sugars / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D020169:Caspases / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003300:Copper; D004249:DNA Damage / Q000187:drug effects*; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers; D005688:Galactosamine / Q000494:pharmacology; D005944:Glucosamine / Q000494:pharmacology; D006595:Hexosamines / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction; D010618:Phenanthrolines / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000606:Amino Sugars; D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D006595:Hexosamines; D010618:Phenanthrolines; C008322:mannosamine; D005688:Galactosamine; D003300:Copper; C002478:bathocuproine; D006861:Hydrogen Peroxide; D020169:Caspases; D005944:Glucosamine