title: Gamma-tocopheryl quinone stimulates apoptosis in drug-sensitive and multidrug-resistant cancer cells.
abstract: Chemotherapy-induced cell death is linked to apoptosis, and there is increasing evidence that multidrug-resistance in cancer cells may be the result of a decrease in the ability of a cell to initiate apoptosis in response to cytotoxic agents. In previous studies, we synthesized two classes of electrophilic tocopheryl quinones (TQ), nonarylating alpha-TQ and arylating gamma- and delta-TQ, and found that gamma- and delta-TQ, but not alpha-TQ, were highly cytotoxic in human acute lymphoblastic leukemia cells (CEM) and multidrug-resistant (MDR) CEM/VLB100. We have now extended these studies on tumor biology with CEM, HL60 and MDR HL60/MX2 human promyelocytic leukemia, U937 human monocytic leukemia, and ZR-75-1 breast adenocarcinoma cells. gamma-TQ, but not alpha-TQ or tocopherols, showed concentration and incubation time-dependent effects on loss of plasma membrane integrity, diminished viable cell number, and stimulation of apoptosis. Its cytotoxicity exceeded that of doxorubicin in HL60/MX2 cells, which express MRP, an MDR-associated protein. Apoptosis was confirmed by TEM, TUNEL, and DNA gel electrophoresis. Kinetic studies showed that an induction period was required to initiate an irreversible multiphase process. Gamma-TQ released mitochondrial cytochrome c to the cytosol, induced the cleavage of poly(ADP-ribose)polymerase, and depleted intracellular glutathione. Unlike xenobiotic electrophiles, gamma-TQ is a highly cytotoxic arylating electrophile that stimulates apoptosis in several cancer cell lines including cells that express MDR through both P-glycoprotein and MRP-associated proteins. The biological properties of arylating TQ electrophiles are closely associated with cytotoxicity and may contribute to other biological effects of these highly active agents.
authors.affiliation: Department of Anatomy and Medical Education, The Ohio State University College of Medicine, Columbus 43210, USA. jones.4@osu.edu
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Jones
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Liu
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Roehm
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Eckel
authors.forename: Tobin T
authors.initials: TT
authors.lastname: Eckel
authors.forename: Chad R
authors.initials: CR
authors.lastname: Stickrath
authors.forename: Craig A
authors.initials: CA
authors.lastname: Triola
authors.forename: Zongcheng
authors.initials: Z
authors.lastname: Jiang
authors.forename: Gianna M
authors.initials: GM
authors.lastname: Bartoli
authors.forename: David G
authors.initials: DG
authors.lastname: Cornwell
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D003574:Cytochrome c Group / Q000378:metabolism; D018432:Drug Resistance, Multiple; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D020287:In Situ Nick-End Labeling; D008854:Microscopy, Electron; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D003574:Cytochrome c Group; D014810:Vitamin E; C002421:tocopherylquinone; D011065:Poly(ADP-ribose) Polymerases; D005978:Glutathione