Morad 2016 J Lipid Res
|Morad SA, Ryan TE, Neufer PD, Zeczycki TN, Davis TS, MacDougall MR, Fox TE, Tan SF, Feith DJ, Loughran TP Jr, Kester M, Claxton DF, Barth BM, Deering TG, Cabot MC (2016) Ceramide-tamoxifen regimen targets bioenergetic elements in acute myelogenous leukemia. J Lipid Res 57:1231-42.|
Abstract: The objective of our study was to determine the mechanism of action of the short-chain ceramide analog, C6-ceramide, and the breast cancer drug, tamoxifen, which we show coactively depress viability and induce apoptosis in human acute myelogenous leukemia cells. Exposure to the C6-ceramide-tamoxifen combination elicited decreases in mitochondrial membrane potential and complex I respiration, increases in reactive oxygen species (ROS), and release of mitochondrial proapoptotic proteins. Decreases in ATP levels, reduced glycolytic capacity, and reduced expression of inhibitors of apoptosis proteins also resulted. Cytotoxicity of the drug combination was mitigated by exposure to antioxidant. Cells metabolized C6-ceramide by glycosylation and hydrolysis, the latter leading to increases in long-chain ceramides. Tamoxifen potently blocked glycosylation of C6-ceramide and long-chain ceramides. N-desmethyltamoxifen, a poor antiestrogen and the major tamoxifen metabolite in humans, was also effective with C6-ceramide, indicating that traditional antiestrogen pathways are not involved in cellular responses. We conclude that cell death is driven by mitochondrial targeting and ROS generation and that tamoxifen enhances the ceramide effect by blocking its metabolism. As depletion of ATP and targeting the "Warburg effect" represent dynamic metabolic insult, this ceramide-containing combination may be of utility in the treatment of leukemia and other cancers.
Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.
Labels: MiParea: Respiration, mt-Membrane, Pharmacology;toxicology Pathology: Cancer Stress:Cell death Organism: Human Tissue;cell: Blood cells, Other cell lines Preparation: Permeabilized cells Enzyme: Complex I
Coupling state: LEAK, OXPHOS Pathway: N, S, NS HRR: Oxygraph-2k