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

• Published in: Lipids Vol. 33; no. 3; pp. 295 - 301
• Main Authors: Cornwell, David G., Jones, Kenneth H., Jiang, Zongcheng, Lantry, Laura E., Southwell‐Keely, Peter, Kohar, Indrajati, Thornton, Donald E.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer‐Verlag 01.03.1998; Springer Nature B.V
• Subjects: Acetylcysteine - pharmacology; Alkylating Agents - toxicity; Buthionine Sulfoximine - pharmacology; Cell Survival - drug effects; Cytotoxicity; Doxorubicin - toxicity; Drug Resistance, Multiple - genetics; Glutathione - metabolism; Humans; Leukemia; Leukemia, Lymphoid - metabolism; Molecular Structure; Quinones - toxicity; Tumor Cells, Cultured; Vitamin E - analogs & derivatives; Vitamin E - toxicity
• ISSN: 0024-4201; 1558-9307
• DOI: 10.1007/s11745-998-0208-8

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.