Institution: | * Department of Medical Biochemistry, The Ohio State University, Columbus, OH, USA † Department of Cell Biology/Neurobiology Anatomy, The Ohio State University, Columbus, OH, USA ‡ Department of Radiology, The Ohio State University, Columbus, OH, USA § Department of Internal Medicine, The Ohio State University, Columbus, OH, USA |
Abstract: | We found previously that d]- -tocopherol ( -T) and d]- -tocopherol ( -T) are lipid antioxidants (thiobarbituric acid test) in model systems containing arachidonic acid (AA), cumene hydroperoxide, and Fe3+ and in smooth muscle cell (SMC) cultures challenged with AA. We now show that d]- -tocopherylquinone ( -TQ), d]-δ-tocopherylquinone (δ-TQ), and d]-γ-tocopherylquinone (γ-TQ) are antioxidants at low concentrations and prooxidants at high concentrations in the model system. Prooxidant activity is greater with γ-TQ than either -TQ or δ-TQ. Low concentrations of -TQ, γ-TQ, and δ-TQ are also antioxidants in SMC cultures challenged with AA. Unlike -TQ, partially substituted γ-TQ and glutathione (GSH) form a Michael adduct which has been purified and characterized. We found previously that -T, γ-T, and -TQ are mitogenic in SMC. We now report that both δ-TQ and δ-TQ but not -TQ show concentration-dependent cytotoxicity (changes in morphology, propidium iodide stain) in SMC cultures. Cytotoxicity is greater with γ-TQ than δ-TQ. An acute lymphoblastic leukemia (ALL) cell line shows greater chemosensitivity (MTF and Neutral Red assays) to γ-TQ than to either doxombicin (DOX) or vinblastine (VLB). An ALL cell line resistant to both DOX and VLB retains the same chemosensitivity to γ-TQ as the drug-sensitive ALL cell line. ALL cell lines are unaffected by either -TQ or the GSH Michael adduct of γ-TQ. These data show that partially substituted tocopheryl quinones capable of forming Michael adducts are potential chemotherapeutic agents for multidrug-resistant cancer cells. |