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 th e phytyl side-chain (PR) were measured in acute lymphoblastic leukemia cell lines that are drug-sensitive (GEM) and multidrug-resistant (CEM /VLB100). Among tocopherols, only delta-T exhibited cytotoxicity. Amon g para quinones, alpha-TQ showed no cytotoxicity, while gamma-TQ and d elta-TQ were highly cytotoxic in both CEM and CEM/VLB100 cell lines (L D50 < 10 mu M). delta-TQ and gamma-TQ were more cytotoxic than the wid ely studied chemotherapeutic agent doxorubicin, which also showed sele ctive cytotoxicity to CEM cells. The orthoquinone Tocored was less cyt otoxic than doxorubicin in drug-sensitive cells but more cytotoxic tha n doxorubicin in multidrug-resistant cells. Cytotoxicity was not a fun ction of the phytyl side-chain since both TMCQ and PR were cytotoxic i n 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 poo l was depleted by preincubation with buthionine-[S,R]-sulfoximine, but cytotoxicity was diminished by the addition of N-acetylcysteine to cu ltures. alpha-T also diminished the cytotoxicity of para- and orthoqui nones. Buthionine-[S,R]-sulfoximine did not block the inhibitory effec t of either N-acetylcysteine or alpha-T, showing that these agents did not act solely by maintaining the glutathione pool as an essential an tioxidant system. In conclusion, tocopherylquinones represent a new cl ass of alkylating electrophilic quinones that function as highly cytot oxic agents and escape multidrug resistance in acute lymphoblastic leu kemia cell lines.