Cytotoxicity of tocopherols and their quinones in drug-sensitive and multidrug-resistant leukemia cells
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Cytotoxicities of tocopherols (α-T, γ-T, δ-T), their para (α-TQ, γ-TQ, δ-TQ)-and ortho (Tocored)-quinone oxidation products, the synthetic quinone analog of γ-TQ containing a methyl group substituted for the phytyl side-chain (TMCQ) and the synthetic quinone analog of Tocored containing a methyl group substituted for the phytyl side-chain (PR) were measured in acute lymphoblastic leukemia cell lines that are drug-sensitive (CEM) and multidrug-resistant (CEM/VLB100). Among tocopherols, only δ-T exhibited cytotoxicity. Among para quinones, α-TQ showed no cytotoxicity, while γ-TQ and δ-TQ were highly cytotoxic in both CEM and CEM/VLB100 cell lines (LD50<10 μM). δ-TQ and γ-TQ were more cytotoxic than the widely studied chemotherapeutic agent doxorubicin, which also showed selective cytotoxicity to CEM cells. The orthoquinone Tocored was less cytotoxic than doxorubicin in drug-sensitive cells but more cytotoxic than doxorubicin in multidrug-resistant cells. Cytotoxicity was not a function of the phytyl side-chain since both TMCQ and PR were cytotoxic in leukemia cells. Cytotoxic para and ortho quinones were electrophiles that formed adducts with nucleophilic thiol groups in glutathione and 2-mercaptoethanol. Cytotoxicity was enhanced when the glutathione pool was depleted by preincubation with buthionine-[S,R]-sulfoximine, but cytotoxicity was diminished by the addition of N-acetylcysteine to cultures. α-T also diminished the cytotoxicity of para- and or-thoquinones. Buthionine-[S,R]-sulfoximine did not block the inhibitory effect of either N-acetylcysteine or α-T, showing that these agents did not act solely by maintaining the glutathione pool as an essential antioxidant system. In conclusion, tocopherylquinones represent a new class of alkylating electrophilic quinones that function as highly cytotoxic agents and escape multidrug resistance in acute lymphoblastic leukemia cell lines.
- Nesaretnam, K., Guthrie, N., Chambers, A.F., and Carroll, K.K. (1995) Effect of Tocotrienols on the Growth of a Human Breast Cancer Cell Line in Culture, Lipids 30, 1139–1143.
- Nesaretnam, K., Stephens, R., Dils, R., and Darbre, P. (1997) The Anti-Proliferative Properties of Tocotrienols Derived from Palm Oil, Sixteenth International Congress on Nutrition, Abstract PW 10.15, p. 67.
- Lindsey, J.A., Zhang, H., Kaseki, H., Morisaki, N., Sato, T., and Cornwell, D.G. (1985) Fatty Acid Metabolism and Cell Proliferation. VII. Antioxidant Effects of Tocopherols and Their Quinones, Lipids 20, 151–157.
- Thornton, D.E., Jones, K.H., Jiang, Z., Zhang, H., Liu, G., and Cornwell, D.G. (1995) Antioxidant and Cytotoxic Tocopheryl Quinones in Normal and Cancer Cells, Free Radical Biol. Med. 18, 963–976. CrossRef
- Mezick, J.A., Settlemire, C.T., Brierley, G.P., Barefield, K.P., Jensen, W.N., and Cornwell, D.G. (1970) Erythrocyte Membrane Interactions with Menadione and the Mechanism of Menadione-Induced Hemolysis, Biochim. Biophys. Acta 219, 361–371. CrossRef
- Rossi, L., Moore, G.A., Orrenius, S., and O'Brien, P.J. (1986) Quinone Toxicity in Hepatocytes Without Oxidative Stress, Arch. Biochem. Biophys. 251, 25–35. CrossRef
- O'Brien, P.J. (1991) Molecular Mechanisms of Quinone Cytotoxicity, Chem. Biol. Interact. 80, 1–41. CrossRef
- Monks, T.J., Hanzlik, R.P., Cohen, G.M., Ross, D., and Graham, D.G. (1992) Quinone Chemistry and Toxicity, Toxicol. Appl. Pharmacol. 112, 2–16. CrossRef
- Guyton, K.Z., Thompson, J.A., and Kensler, T.W. (1993) Role of Quinone Methide in the In Vitro Toxicity of the Skin Tumor Promoter Butylated Hydroxytoluene Hydroperoxide, Chem. Res. Toxicol. 6, 731–738. CrossRef
- Sharma, M., and Tomasz, M. (1994) Conjugation of Glutathione and Other Thiols with Bioreductively Activated Mitomycin C. Effect of Thiols on the Reductive Activation Rate, Chem. Res. Toxicol. 7, 390–400. CrossRef
- Meister, A. (1988) Glutathione Metabolism and Its Selective Modification, J. Biol. Chem. 263, 17205–17208.
- John, W., Dietzel, E., and Emte, W. (1939) Über Einige Oxydationsprodukte der Tokopherole und Analoger Einfacher Modelkörper. 6. Mitteilung über Antisterilitäts Factoren (vitamin E), Z. Physiol. Chem. 257, 173–189.
- Suarna, C., Baca, M., Craig, D.C., Scudder, M., and Southwell-Keely, P.T. (1991) Further Oxidation Products of 2,2,5,7,8-Pentamethyl-6-chromanol, Lipids 26, 847–852.
- Kohar, I., Baca, M., Suarna, C., Stocker, R., and Southwell-Keely, P.T. (1995) Is α-Tocopherol a Reservoir for α-Tocopheryl Hydroquinone? Free Radical Biol. Med. 19, 197–207. CrossRef
- Lau, S.S., Hill, B.A., and Highet, R.J. (1988) Sequential Oxidation and Glutathione Addition to 1,4-Benzoquinone. Correlation of Toxicity with Increased Glutathione Substitution, Molec. Pharmacol. 34, 829–836.
- Smithgall, T.E., Harvey, R.G., and Penning, T.M. (1988) Spectroscopic Identification of Ortho-quinones as the Products of Polycyclic Aromatic trans-Dihydrodiol Oxidation Catalyzed by Dihydrodiol Dehydrogenase, J. Biol. Chem. 263, 1814–1820.
- Carmichael, J., DeGraff, W.G., Gazder, A.F., Minna, J.D., and Mitchell, J.B. (1987) Evaluation of a Tetrazolium-based Semiautomated Colorimetric Assay: Assessment of Chemosensitivity Testing, Cancer Res. 47, 936–942.
- Berridge, M.V., Tan, A.S., McCoy, K.D., and Wang, R. (1996) The Biochemical and Cellular Basis of Cell Proliferation Assays That Use Tetrazolium Salts, Biochemica 4, 14–19.
- Butler, J., and Hoey, B.M. (1992) Reactions of Glutathione and Glutathione Radicals with Benzoquinones, Free Radical Biol. Med. 12, 337–345. CrossRef
- Pacht, E.R., Kaseki, H., Mohammed, J.R., Cornwell, D.G., and Davis, W.B. (1986) Deficiency of Vitamin E in the Alveolar Fluid of Cigarette Smokers. Influence on Alveolar Macrophage Cytotoxicity, J. Clin. Invest. 77, 789–796. CrossRef
- Csallany, A.S., Draper, H.H., and Shah, S.N. (1962) Conversion of d-α-Tocopherol-C14 to Tocopheryl-p-quinone in vivo. Arch. Biochem. Biophys. 98, 142–145. CrossRef
- Mellors, A., and Barnes, M.Mc. (1966) The Distribution and Metabolism of α-Tocopherol in the Rat, Br. J. Nutr. 20, 69–77. CrossRef
- Peake, I.R., and Bieri, J.G. (1971) Alpha- and Gamma-tocopherol in the Rat: in vitro and in vivo Tissue Uptake and Metabolism, J. Nutr. 101, 1615–1622.
- Gallo Torres, H.E., Miller, O.N., Hamilton, J.G., and Tratnyek, C. (1971) Distribution and Metabolism of Two Orally Administered Esters of Tocopherol, Lipids 6, 318–325.
- Ham, A-J.L., and Liebler, D.C. (1995) Vitamin E Oxidation in Rat Liver Mitochondria, Biochemistry 34, 5754–5761. CrossRef
- Cooney, R.V., Harwood, P.J., Franke, A.A., Narala, K., Sundström, A.-K., Berggren, P.-O., and Mordan, L.J. (1995) Products of γ-Tocopherol Reaction with NO2 and Their Formation in Rat Insulinoma (RINm5F) Cells, Free Radical Biol. Med. 19, 259–269. CrossRef
- Christen, S., Woodall, A.A., Shigenaga, M.K., Southwell-Keely, P.T., Duncan, M.W., and Ames, B.N. (1997) γ-Tocopherol Traps Mutagenic Electrophiles Such as NO and Complements α-Tocopherol: Physiological Implications, Proc. Natl. Acad. Sci. USA 94, 3217–3222. CrossRef
- Siegel, D., Bolton, E.M., Burr, J.A., Liebler, D.C., and Ross, D. (1997) The Reduction of α-Tocopherolquinone by Human NAD(P)H: Quinone Oxidoreductase: The Role of α-Tocopherolhydroquinone as a Cellular Antioxidant, Molec. Pharmacol. 52, 300–305.
- DeLong, M.J., Prochaska, H.J., and Talalay, P. (1986) Induction of NAD(P)H: Quinone Reductase in Murine Hepatoma Cells by Phenolic Antioxidants, Dyes, and Other Azo Chemoprotectors: A Model System for the Study of Anticarcinogens, Proc. Natl. Acad. Sci. USA 83, 787–791. CrossRef
- Kayden, H.J., and Traber, M.G. (1993) Absorption, Lipoprotein Transport and Regulation of Plasma Concentrations of Vitamin E in Humans, J. Lipid Res. 34, 343–358.
- Behrens, W.A., and Madere, R. (1986) α- and γ-Tocopherol Concentrations in Human Serum, J. Am. Coll. Nutr. 5, 91–96.
- Podda, M., Weber, C., Traber, M., and Packer, L. (1996) Simultaneous Determination of Tissue Tocopherols, Tocotrienols, Ubiquinols, and Ubiquinones, J. Lipid Res. 37, 893–901.
- Cytotoxicity of tocopherols and their quinones in drug-sensitive and multidrug-resistant leukemia cells
Volume 33, Issue 3 , pp 295-301
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- 1. Department of Medical Biochemistry, The Ohio State University, 333 Hamilton Hall, 1645 Neil Ave., 43210, Columbus, Ohio
- 2. Department of Cell Biology/Neurobiology/Anatomy, The Ohio State University, 333 Hamilton Hall, 1645 Neil Ave., 43210, Columbus, Ohio
- 3. Department of Radiology, The Ohio State University, 333 Hamilton Hall, 1645 Neil Ave., 43210, Columbus, Ohio
- 4. Internal Medicine, The Ohio State University, 333 Hamilton Hall, 1645 Neil Ave., 43210, Columbus, Ohio
- 5. Department of Organic Chemistry, The University of New South Wales, Sydney, Australia
- 6. Faculty of Pharmacy, University of Surabaya, Jawa Timor, Indonesia