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.
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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
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Cornwell, D.G., Jones, K.H., Jiang, Z. et al. Cytotoxicity of tocopherols and their quinones in drug-sensitive and multidrug-resistant leukemia cells. Lipids 33, 295–301 (1998). https://doi.org/10.1007/s11745-998-0208-8
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DOI: https://doi.org/10.1007/s11745-998-0208-8