γ‐Tocopheryl quinone stimulates apoptosis in drug‐sensitive and multidrug‐resistant cancer cells

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/VLB100. 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.