Modification of sphingolipid metabolism by tamoxifen and N-desmethyltamoxifen in acute myelogenous leukemia--Impact on enzyme activity and response to cytotoxics

Biochimica Et Biophysica Acta
Samy A F MoradM C Cabot

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...Continue Reading

References

Aug 9, 1996·The Journal of Biological Chemistry·Y LavieM C Cabot
May 18, 1999·The Journal of Biological Chemistry·L LeeJ A Shayman
Mar 18, 2000·The Journal of Biological Chemistry·D K PerryY A Hannun
Jun 17, 2000·Biochimica Et Biophysica Acta·P BorstA van Helvoort
Mar 10, 2001·Journal of the National Cancer Institute·A SenchenkovM C Cabot
Jun 8, 2001·International Journal of Cancer. Journal International Du Cancer·R S Olshefski, S Ladisch
Feb 19, 2004·The Journal of Biological Chemistry·Francesca ScarlattiPatrice Codogno
Jul 21, 2004·The Journal of Biological Chemistry·Edward Norris-CervettoTerry D Butters
Mar 17, 2007·Chembiochem : a European Journal of Chemical Biology·Carmen BediaGemma Fabriàs
May 17, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Harikrishna DevalapallyMansoor M Amiji
May 21, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Banu S ZolnikScott E McNeil
Aug 12, 2008·Current Drug Targets·Youssef H ZeidanYusuf A Hannun
Nov 26, 2008·The Journal of Biological Chemistry·Sophie PattingrePatrice Codogno
Apr 14, 2010·Biochemical Pharmacology·Jacqueline V ChapmanMyles C Cabot
Nov 3, 2010·International Journal of Oncology·Jacqueline V ChapmanMyles C Cabot
Nov 12, 2010·Journal of Lipid Research·Todd E FoxMark Kester
Jun 28, 2011·The Journal of Biological Chemistry·Carmen BediaThierry Levade
Jun 29, 2011·Anti-cancer Agents in Medicinal Chemistry·Brian M BarthMark Kester
Jun 29, 2011·Anti-cancer Agents in Medicinal Chemistry·Valerie Gouaze-Andersson, Myles C Cabot
Dec 25, 2012·Cancer Chemotherapy and Pharmacology·Samy A F MoradMyles C Cabot
Feb 21, 2013·Journal of Lipid Research·Luz CamachoTimothy M Thomson
Aug 14, 2013·Biochimica Et Biophysica Acta·Samy A F MoradMyles C Cabot
Jan 5, 2014·Biochimica Et Biophysica Acta·Jean-Philip TrumanYusuf A Hannun

❮ Previous
Next ❯

Citations

May 13, 2015·Biochimica Et Biophysica Acta·Samy A F Morad, Myles C Cabot
Apr 25, 2017·Expert Opinion on Therapeutic Targets·Su-Fern TanThomas P Loughran
May 4, 2016·Journal of Lipid Research·Samy A F MoradMyles C Cabot
Dec 22, 2017·Signal Transduction and Targeted Therapy·Ushma A DoshiMark Kester
Nov 21, 2019·Molecular Cancer Research : MCR·Jennifer M PearsonThomas P Loughran
Jan 7, 2021·Omics : a Journal of Integrative Biology·Medi KoriKazim Yalcin Arga
Aug 28, 2021·International Journal of Molecular Sciences·Miguel Olivas-AguirreOxana Dobrovinskaya

❮ Previous
Next ❯

Related Concepts

Related Feeds

Blood And Marrow Transplantation

The use of hematopoietic stem cell transplantation or blood and marrow transplantation (bmt) is on the increase worldwide. BMT is used to replace damaged or destroyed bone marrow with healthy bone marrow stem cells. Here is the latest research on bone and marrow transplantation.

AML: Role of LSD1 by CRISPR (Keystone)

Find the latest rersearrch on the ability of CRISPR-Cas9 mutagenesis to profile the interactions between lysine-specific histone demethylase 1 (LSD1) and chemical inhibitors in the context of acute myeloid leukemia (AML) here.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous disease with approximately 20,000 cases per year in the United States. AML also accounts for 15-20% of all childhood acute leukemias, while it is responsible for more than half of the leukemic deaths in these patients. Here is the latest research on this disease.