ANTIOXIDANT AND CYTOTOXIC TOCOPHERYL QUINONES IN NORMAL AND CANCER-CELLS

We found previously that [d]-alpha-tocopherol (alpha-T) and [d]-gamma- tocopherol (gamma-T) are lipid antioxidants (thiobarbituric acid test) in model systems containing arachidonic acid (AA), cumene hydroperoxi de, and Fe3+ and in smooth muscle cell (SMC) cultures challenged with AA. We now show that [d]-alpha-tocopherylquinone (alpha-TQ), [d]-delta -tocopherylquinone (delta-TQ), and [d]-gamma-tocopherylquinone (gamma- TQ) are antioxidants at low concentrations and prooxidants at high con centrations in the model system. Prooxidant activity is greater with g amma-TQ than either alpha-TQ or delta-TQ. Low concentrations of alpha- TQ, delta-TQ, and gamma-TQ are also antioxidants in SMC cultures chall enged with AA. Unlike alpha-TQ, partially substituted gamma-TQ and glu tathione (GSH) form a Michael adduct which has been purified and chara cterized. We found previously that alpha-T, gamma-T, and (alpha-TQ are mitogenic in SMC. We now report that both delta-TQ and gamma-TQ but n ot alpha-TQ show concentration-dependent cytotoxicity (changes in morp hology, propidium iodide stain) in SMC cultures. Cytotoxicity is great er with gamma-TQ than delta-TQ. An acute lymphoblastic leukemia (ALL) cell line shows greater chemosensitivity (MTT and Neutral Red assays) to gamma-TQ than to either doxorubicin (DOX) or vinblastine (VLB). An ALL cell line resistant to both DOX and VLB retains the same chemosens itivity to gamma-TQ as the drug-sensitive ALL cell line. ALL cell line s are unaffected by either alpha-TQ or the GSH Michael adduct of gamma -TQ. These data show that partially substituted tocopheryl quinones ca pable of forming Michael adducts are potential chemotherapeutic agents for multidrug-resistant cancer cells.