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

• Published in: FEBS letters Vol. 580; no. 19; pp. 4751 - 4756
• Main Authors: Elojeimy, Saeed, Holman, David H., Liu, Xiang, El-Zawahry, Ahmed, Villani, Maristella, Cheng, Joseph C., Mahdy, Ayman, Zeidan, Youssef, Bielwaska, Alicja, Hannun, Yusuf A., Norris, James S.
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 21.08.2006
• Subjects: Acid ceramidase; Acid sphingomyelinase; Antidepressive Agents, Tricyclic - pharmacology; Cationic amphiphilic drugs; Cell Line, Tumor; Ceramide; Cysteine Endopeptidases - metabolism; Desipramine; Desipramine - pharmacology; Enzyme Inhibitors - pharmacology; Galactosylgalactosylglucosylceramidase - antagonists & inhibitors; Humans; Hydrolysis; Male; Reverse Transcriptase Polymerase Chain Reaction; Sphingolipids - metabolism; Sphingomyelin; Ceramide; Sphingomyelin; Acid ceramidase; Desipramine; Cationic amphiphilic drugs; Acid sphingomyelinase
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2006.07.071

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.