Antioxidant and cytotoxic tocopheryl quinones in normal and cancer cells

We found previously that [d]-α-tocopherol (α-T) and [d]-α-tocopherol (α-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]-α-tocopherylquinone (α-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 α-TQ or δ-TQ. Low concentrations of α-TQ, γ-TQ, and δ-TQ are also antioxidants in SMC cultures challenged with AA. Unlike α-TQ, partially substituted γ-TQ and glutathione (GSH) form a Michael adduct which has been purified and characterized. We found previously that α-T, γ-T, and α-TQ are mitogenic in SMC. We now report that both δ-TQ and δ-TQ but not α-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 α-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.