Cytotoxicity of tocopherols and their quinones in drug-sensitive and multidrug-resistant leukemia cells.
Cytotoxicities of tocopherols (alpha-T, gamma-T, delta-t), their para (alpha-TQ, gamma-TQ, delta-TQ)- and ortho (Tocored)-quinone oxidation products, the synthetic quinone analog of gamma-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 delta-T exhibited cytotoxicity. Among para quinones, alpha-TQ showed no cytotoxicity, while gamma-TQ and delta-TQ were highly cytotoxic in both CEM and CEM/VLB100 cell lines (LD50 < 10 muM). delta-TQ and gamma-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. alpha-T also diminished the cytotoxicity of para- and orthoquinones. Buthionine-[S,R]-sulfoximine did not block the inhibitory effect of either N-acetylcysteine or alpha-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.
Cornwell
D G
DG
Department of Medical Biochemistry, Ohio State University, Columbus 43210, USA. dcornwel@smtp.med.ohio-state.edu
Jones
K H
KH
Jiang
Z
Z
Lantry
L E
LE
Southwell-Keely
P
P
Kohar
I
I
Thornton
D E
DE
D000111:Acetylcysteine / Q000494:pharmacology; D000477:Alkylating Agents / Q000633:toxicity; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007945:Leukemia, Lymphoid / Q000378:metabolism; D015394:Molecular Structure; D011809:Quinones / Q000633:toxicity; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000031:analogs & derivatives / Q000633:toxicity*
D000477:Alkylating Agents; D011809:Quinones; D014810:Vitamin E; D019328:Buthionine Sulfoximine; D004317:Doxorubicin; D005978:Glutathione; D000111:Acetylcysteine