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Gamma-tocopheryl quinone stimulates apoptosis in drug-sensitive and multidrug-resistant cancer cells
Kenneth H Jones1, Jennifer J Liu, Jennifer S Roehm
1Department of Anatomy and Medical Education, The Ohio State University College of Medicine, Columbus 43210, USA. jones.4@osu.edu
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.
Insights
Arylating gamma-tocopheryl quinones (TQ) demonstrate potent anticancer activity by inducing apoptosis in various cancer cells, including multidrug-resistant (MDR) lines. These compounds offer a promising therapeutic strategy against resistant cancers.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Multidrug resistance (MDR) in cancer is often linked to impaired apoptosis.
- Tocopheryl quinones (TQ) are derivatives of vitamin E with potential cytotoxic properties.
Purpose of the Study:
- To investigate the cytotoxic effects and apoptosis-inducing potential of different TQ classes on various human cancer cell lines.
- To evaluate the efficacy of arylating gamma-TQ against MDR cancer cells expressing P-glycoprotein and MRP proteins.
Main Methods:
- Cell viability assays, plasma membrane integrity tests, and apoptosis assays (TEM, TUNEL, DNA gel electrophoresis) were performed.
- Kinetic studies and analysis of apoptosis markers like cytochrome c release and PARP cleavage were conducted.
- Cytotoxicity was compared to doxorubicin in MRP-expressing cells.
Main Results:
- Arylating gamma- and delta-TQ, but not alpha-TQ or tocopherols, exhibited significant cytotoxicity and stimulated apoptosis in multiple cancer cell lines.
- Gamma-TQ demonstrated concentration and time-dependent effects, including loss of membrane integrity and reduced viable cell number.
- Gamma-TQ's cytotoxicity surpassed doxorubicin in HL60/MX2 cells, and it induced key apoptotic events like cytochrome c release and PARP cleavage.
Conclusions:
- Arylating TQ, particularly gamma-TQ, are potent cytotoxic agents that effectively induce apoptosis in diverse cancer cell lines.
- Gamma-TQ overcomes MDR mechanisms mediated by P-glycoprotein and MRP, showing promise for treating resistant cancers.
- The cytotoxic and apoptosis-stimulating properties of arylating TQ are linked to their electrophilic nature and may have broader therapeutic implications.