New insights on the use of desipramine as an inhibitor for acid ceramidase.
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.
Elojeimy
Saeed
S
Department of Microbiology and Immunology, Medical University of South Carolina, P.O. Box 250504, 173 Ashley Avenue, Charleston, SC 29425, USA.
Holman
David H
DH
Liu
Xiang
X
El-Zawahry
Ahmed
A
Villani
Maristella
M
Cheng
Joseph C
JC
Mahdy
Ayman
A
Zeidan
Youssef
Y
Bielwaska
Alicja
A
Hannun
Yusuf A
YA
Norris
James S
JS
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
D000929:Antidepressive Agents, Tricyclic; D004791:Enzyme Inhibitors; D013107:Sphingolipids; D002517:Galactosylgalactosylglucosylceramidase; D003546:Cysteine Endopeptidases; D003891:Desipramine