title: Antioxidant and cytotoxic tocopheryl quinones in normal and cancer cells.
abstract: 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 hydroperoxide, 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 concentrations in the model system. Prooxidant activity is greater with gamma-TQ than either alpha-TQ or delta-TQ. Low concentrations of alpha-TQ, delta-TQ, and gamma-TQ are also antioxidants in SMC cultures challenged with AA. Unlike alpha-TQ, partially substituted gamma-TQ and glutathione (GSH) form a Michael adduct which has been purified and characterized. 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 not alpha-TQ show concentration-dependent cytotoxicity (changes in morphology, propidium iodide stain) in SMC cultures. Cytotoxicity is greater 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 chemosensitivity to gamma-TQ as the drug-sensitive ALL cell line. ALL cell lines are unaffected by either alpha-TQ or the GSH Michael adduct of gamma-TQ. These data show that partially substituted tocopheryl quinones capable of forming Michael adducts are potential chemotherapeutic agents for multidrug-resistant cancer cells.
authors.affiliation: Department of Medical Biochemistry, Ohio State University, Columbus 43210, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Thornton
authors.forename: K H
authors.initials: KH
authors.lastname: Jones
authors.forename: Z
authors.initials: Z
authors.lastname: Jiang
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: G
authors.initials: G
authors.lastname: Liu
authors.forename: D G
authors.initials: DG
authors.lastname: Cornwell
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000494:pharmacology; D001555:Benzene Derivatives / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005978:Glutathione / Q000737:chemistry; D006168:Guinea Pigs; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology; D011809:Quinones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D001555:Benzene Derivatives; D011809:Quinones; D014810:Vitamin E; D016718:Arachidonic Acid; C002421:tocopherylquinone; D005978:Glutathione; C007164:cumene hydroperoxide