New insights on the use of desipramine as an inhibitor for acid ceramidase

Saeed Elojeimy, David H. Holman, Xiang Liu, Ahmed El-Zawahry, Maristella Villani, Joseph C. Cheng, Ayman Mahdy, Youssef Zeidan, Alicja Bielwaska, Yusuf A. Hannun, James S. Norris

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

Treatment of different cancer cell lines with desipramine induced a time- and dose-dependent downregulation of acid ceramidase. Desipramine's effect on acid ceramidase appeared specific for amphiphilic agents (desipramine, chlorpromazine, and chloroquine) but not other lysomotropic agents such as ammonium chloride and bafilomycin A1, and was not transcriptionally regulated. The cathepsin B/L inhibitor, CA074ME, but not the cathepsin D inhibitor, pepstatin A, blocked desipramine's effect on acid ceramidase. Desipramine led to a more pronounced downregulation of sphingosine compared to ceramide suggesting acid ceramidase inhibition is important to desipramine's mechanism of action. This study reveals a new mechanism of action for desipramine.

Original languageEnglish (US)
Pages (from-to)4751-4756
Number of pages6
JournalFEBS letters
Volume580
Issue number19
DOIs
StatePublished - Aug 21 2006

Keywords

  • Acid ceramidase
  • Acid sphingomyelinase
  • Cationic amphiphilic drugs
  • Ceramide
  • Desipramine
  • Sphingomyelin

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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    Elojeimy, S., Holman, D. H., Liu, X., El-Zawahry, A., Villani, M., Cheng, J. C., Mahdy, A., Zeidan, Y., Bielwaska, A., Hannun, Y. A., & Norris, J. S. (2006). New insights on the use of desipramine as an inhibitor for acid ceramidase. FEBS letters, 580(19), 4751-4756. https://doi.org/10.1016/j.febslet.2006.07.071