[gamma]-Tocopheryl quinone stimulates apoptosis in drug-sensitive and multidrug-resistant cancer cells

• Published in: Lipids Vol. 37; no. 2; p. 173
• Main Authors: Jones, Kenneth H, Liu, Jennifer J, Roehm, Jennifer S, Eckel, Jason J, Eckel, Tobin T, Stickrath, Chad R, Triola, Craig A, Jiang, Zongcheng, Bartoli, Gianna M, Cornwell, David G
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer Nature B.V 01-02-2002
• Subjects: Adenosine diphosphate; Apoptosis; Biological effects; Biological properties; Cancer; Cells; Cytotoxicity; Drug resistance; Leukemia
• ISSN: 0024-4201; 1558-9307
• DOI: 10.1007/s11745-002-0878-2

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 α-TQ and arylating γ-and δ-TQ, and found that γ-and δ-TQ, but not α-TQ, were highly cytotoxic in human acute lymphoblastic leukemia cells (CEM) and multidrug-resistant (MDR) CEM/VLB^sub 100^. We have now extended these studies on tumor biology with CFM, HL60 and MDR HL60/MX2 human promyelocytic leukemia, U937 human monocytic leukemia, and ZR-75-1 breast adenocarcinoma cells. γ-TQ, but not α-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. γ-TQ released mitochondrial cytochrome c to the cytosol, induced the cleavage of poly(ADP-ribose)polymerase, and depleted intracellular glutathione. Unlike xenobiotic electrophiles, γ-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.[PUBLICATION ABSTRACT]