Ceramide-tamoxifen regimen targets bioenergetic elements in acute myelogenous leukemia

Samy A.F. Morad, Terence E. Ryan, P. Darrell Neufer, Tonya N. Zeczycki, Traci S. Davis, Matthew R. MacDougall, Todd E. Fox, Su Fern Tan, David J. Feith, Thomas P. Loughran, Mark Kester, David F. Claxton, Brian M. Barth, Tye G. Deering, Myles C. Cabot

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1231-1242
Number of pages12
JournalJournal of Lipid Research
Volume57
Issue number7
DOIs
StatePublished - Jul 2016

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Ceramides
Tamoxifen
Acute Myeloid Leukemia
Energy Metabolism
Glycosylation
Estrogen Receptor Modulators
Reactive Oxygen Species
Adenosine Triphosphate
Inhibitor of Apoptosis Proteins
Mitochondrial Membrane Potential
Mitochondrial Proteins
Cell death
Drug Combinations
Cytotoxicity
Metabolites
Metabolism
Hydrolysis
Respiration
Leukemia
Cell Death

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Endocrinology
  • Cell Biology

Cite this

Morad, S. A. F., Ryan, T. E., Neufer, P. D., Zeczycki, T. N., Davis, T. S., MacDougall, M. R., ... Cabot, M. C. (2016). Ceramide-tamoxifen regimen targets bioenergetic elements in acute myelogenous leukemia. Journal of Lipid Research, 57(7), 1231-1242. https://doi.org/10.1194/jlr.M067389
Morad, Samy A.F. ; Ryan, Terence E. ; Neufer, P. Darrell ; Zeczycki, Tonya N. ; Davis, Traci S. ; MacDougall, Matthew R. ; Fox, Todd E. ; Tan, Su Fern ; Feith, David J. ; Loughran, Thomas P. ; Kester, Mark ; Claxton, David F. ; Barth, Brian M. ; Deering, Tye G. ; Cabot, Myles C. / Ceramide-tamoxifen regimen targets bioenergetic elements in acute myelogenous leukemia. In: Journal of Lipid Research. 2016 ; Vol. 57, No. 7. pp. 1231-1242.
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Morad, SAF, Ryan, TE, Neufer, PD, Zeczycki, TN, Davis, TS, MacDougall, MR, Fox, TE, Tan, SF, Feith, DJ, Loughran, TP, Kester, M, Claxton, DF, Barth, BM, Deering, TG & Cabot, MC 2016, 'Ceramide-tamoxifen regimen targets bioenergetic elements in acute myelogenous leukemia', Journal of Lipid Research, vol. 57, no. 7, pp. 1231-1242. https://doi.org/10.1194/jlr.M067389

Ceramide-tamoxifen regimen targets bioenergetic elements in acute myelogenous leukemia. / Morad, Samy A.F.; Ryan, Terence E.; Neufer, P. Darrell; Zeczycki, Tonya N.; Davis, Traci S.; MacDougall, Matthew R.; Fox, Todd E.; Tan, Su Fern; Feith, David J.; Loughran, Thomas P.; Kester, Mark; Claxton, David F.; Barth, Brian M.; Deering, Tye G.; Cabot, Myles C.

In: Journal of Lipid Research, Vol. 57, No. 7, 07.2016, p. 1231-1242.

Research output: Contribution to journalArticle

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T1 - Ceramide-tamoxifen regimen targets bioenergetic elements in acute myelogenous leukemia

AU - Morad, Samy A.F.

AU - Ryan, Terence E.

AU - Neufer, P. Darrell

AU - Zeczycki, Tonya N.

AU - Davis, Traci S.

AU - MacDougall, Matthew R.

AU - Fox, Todd E.

AU - Tan, Su Fern

AU - Feith, David J.

AU - Loughran, Thomas P.

AU - Kester, Mark

AU - Claxton, David F.

AU - Barth, Brian M.

AU - Deering, Tye G.

AU - Cabot, Myles C.

PY - 2016/7

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Morad SAF, Ryan TE, Neufer PD, Zeczycki TN, Davis TS, MacDougall MR et al. Ceramide-tamoxifen regimen targets bioenergetic elements in acute myelogenous leukemia. Journal of Lipid Research. 2016 Jul;57(7):1231-1242. https://doi.org/10.1194/jlr.M067389