Lipids

, Volume 33, Issue 3, pp 295–301

Cytotoxicity of tocopherols and their quinones in drug-sensitive and multidrug-resistant leukemia cells

Authors

    • Department of Medical BiochemistryThe Ohio State University
  • Kenneth H. Jones
    • Department of Cell Biology/Neurobiology/AnatomyThe Ohio State University
  • Zongcheng Jiang
    • Department of RadiologyThe Ohio State University
  • Laura E. Lantry
    • Internal MedicineThe Ohio State University
  • Peter Southwell-Keely
    • Department of Organic ChemistryThe University of New South Wales
  • Indrajati Kohar
    • Faculty of PharmacyUniversity of Surabaya
  • Donald E. Thornton
    • Internal MedicineThe Ohio State University
Article

DOI: 10.1007/s11745-998-0208-8

Cite this article as:
Cornwell, D.G., Jones, K.H., Jiang, Z. et al. Lipids (1998) 33: 295. doi:10.1007/s11745-998-0208-8

Abstract

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.

Abbreviations

ANOVA

analysis of variance

BSO

buthionine-[S,R]-sulfoximine

CEM

drug-sensitive lymphoblastic leukemia cells

CEM/VLB100

multidrug-resistant lymphoblastic leukemia cells

FAB MS

fast atom bombardment mass spectrometry

HPLC

high-performance liquid chromatography

MTT

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NAC

N-acetylcysteine

PR

2,2,7,8-tetramethylchroman-5,6-dione

α-T, δ-T

and γ-T, α-, δ- and γ-tocopherol

TLC

thin-layer chromatography

TMCQ

2-(3-hydroxy-3-methylbutyl)-5,6-dimethyl-1,4-benzoquinone

Tocored

2,7,8-trimethyl-2-(4,8,12-trimethyldecyl)0chroman-5,6-dione

TQ

tocopheryl quinone

α-TQ

γ-TQ, and δ-TQ, α-, γ-, and δ-tocopheryl quinone

Copyright information

© AOCS Press 1998