ArticleBiochimica et biophysica acta2015
Modification of sphingolipid metabolism by tamoxifen and N-desmethyltamoxifen in acute myelogenous leukemia--Impact on enzyme activity and response to cytotoxics.
Article in Biochimica et biophysica acta, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 28 citations in OpenAlex.
- Compared Antileishmanial Activity of Clomiphene and Tamoxifen.Biomedicines · 2024Article
- Fanning the Flames of Endoplasmic Reticulum (ER) Stress: Can Sphingolipid Metabolism Be Targeted to Enhance ER Stress-Associated Immunogenic Cell Death in Cancer?Molecular pharmacology · 2024Review
- Lipidome and metabolome analyses reveal metabolic alterations associated with MCF-7 apoptosis upon 4-hydroxytamoxifen treatment.Scientific reports · 2023Article
- Identification of Potential Treatments for Acute Lymphoblastic Leukemia through Integrated Genomic Network Analysis.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Emerging Roles of Ceramides in Breast Cancer Biology and Therapy.International journal of molecular sciences · 2022Review
- Alterations in sphingolipid composition and mitochondrial bioenergetics represent synergistic therapeutic vulnerabilities linked to multidrug resistance in leukemia.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Article
- Antileishmanial Activity of Tamoxifen by Targeting Sphingolipid Metabolism: A Review.Clinical pharmacology : advances and applications · 2022Review
- Tamoxifen Sensitizes Acute Lymphoblastic Leukemia Cells to Cannabidiol by Targeting Cyclophilin-D and Altering Mitochondrial CaInternational journal of molecular sciences · 2021Article
- Ceramide Analogue SACLAC Modulates Sphingolipid Levels andMolecular cancer research : MCR · 2020Article
- Pivotal role of mitophagy in response of acute myelogenous leukemia to a ceramide-tamoxifen-containing drug regimen.Experimental cell research · 2019Article
- Targeting sphingolipid metabolism as an approach for combination therapies in haematological malignancies.Cell death discovery · 2018Article
- Visualization of ceramide channels in lysosomes following endogenous palmitoyl-ceramide accumulation as an initial step in the induction of necrosis.Biochemistry and biophysics reports · 2017Article
- The emergence of acid ceramidase as a therapeutic target for acute myeloid leukemia.Expert opinion on therapeutic targets · 2017Review
- Role of P-glycoprotein inhibitors in ceramide-based therapeutics for treatment of cancer.Biochemical pharmacology · 2017Article
- Ceramide-tamoxifen regimen targets bioenergetic elements in acute myelogenous leukemia.Journal of lipid research · 2016Article
- Glucosylated cholesterol in mammalian cells and tissues: formation and degradation by multiple cellular β-glucosidases.Journal of lipid research · 2016Article
- Dynamics of ceramide generation and metabolism in response to fenretinide--Diversity within and among leukemia.Leukemia research · 2015Article
- Tamoxifen regulation of sphingolipid metabolism--Therapeutic implications.Biochimica et biophysica acta · 2015Review
- STAT3 mediates C6-ceramide-induced cell death in chronic lymphocytic leukemia.Signal transduction and targeted therapyArticle
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Authors and funding
9 authors at 4 institutions in 1 country.
Funding
Abstract
The triphenylethylene antiestrogen, tamoxifen, can be an effective inhibitor of sphingolipid metabolism. This off-target activity makes tamoxifen an interesting ancillary for boosting the apoptosis-inducing properties of ceramide, a sphingolipid with valuable tumor censoring activity. Here we show for the first time that tamoxifen and metabolite, N-desmethyltamoxifen (DMT), block ceramide glycosylation and inhibit ceramide hydrolysis (by acid ceramidase, AC) in human acute myelogenous leukemia (AML) cell lines and in AML cells derived from patients. Tamoxifen (1-10 μM) inhibition of AC in AML cells was accompanied by decreases in AC protein expression. Tamoxifen also depressed expression and activity of sphingosine kinase 1 (SphK1), the enzyme-catalyzing production of mitogenic sphingosine 1-phosphate (S1-P). Results from mass spectroscopy showed that tamoxifen and DMT (i) increased the levels of endogenous C16:0 and C24:1 ceramide molecular species, (ii) nearly totally halted production of respective glucosylceramide (GC) molecular species, (iii) drastically reduced levels of sphingosine (to 9% of control), and (iv) reduced levels of S1-P by 85%, in vincristine-resistant HL-60/VCR cells. The co-administration of tamoxifen with either N-(4-hydroxyphenyl)retinamide (4-HPR), a ceramide-generating retinoid, or a cell-deliverable form of ceramide, C6-ceramide, resulted in marked decreases in HL-60/VCR cell viability that far exceeded single agent potency. Combination treatments resulted in synergistic apoptotic cell death as gauged by increased Annexin V binding and DNA fragmentation and activation of caspase-3. These results show the versatility of adjuvant triphenylethylene with ceramide-centric therapies for magnifying therapeutic potential in AML. Such drug regimens could serve as effective strategies, even in the multidrug-resistant setting.
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