title: New insights on the use of desipramine as an inhibitor for acid ceramidase.
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.
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, P.O. Box 250504, 173 Ashley Avenue, Charleston, SC 29425, USA.
authors.forename: Saeed
authors.initials: S
authors.lastname: Elojeimy
authors.forename: David H
authors.initials: DH
authors.lastname: Holman
authors.forename: Xiang
authors.initials: X
authors.lastname: Liu
authors.forename: Ahmed
authors.initials: A
authors.lastname: El-Zawahry
authors.forename: Maristella
authors.initials: M
authors.lastname: Villani
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Cheng
authors.forename: Ayman
authors.initials: A
authors.lastname: Mahdy
authors.forename: Youssef
authors.initials: Y
authors.lastname: Zeidan
authors.forename: Alicja
authors.initials: A
authors.lastname: Bielwaska
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
authors.forename: James S
authors.initials: JS
authors.lastname: Norris
mesh_terms: D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003891:Desipramine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D002517:Galactosylgalactosylglucosylceramidase / Q000037:antagonists & inhibitors*; D006801:Humans; D006868:Hydrolysis; D008297:Male; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013107:Sphingolipids / Q000378:metabolism
chemical_list: D000929:Antidepressive Agents, Tricyclic; D004791:Enzyme Inhibitors; D013107:Sphingolipids; D002517:Galactosylgalactosylglucosylceramidase; D003546:Cysteine Endopeptidases; D003891:Desipramine