Gilenya (FTY720) inhibits acid sphingomyelinase by a mechanism similar to tricyclic antidepressants.
The immunomodulator drug Gilenya (FTY720), marketed as the first oral sphingosine-1-phosphate receptor (S1P-R) modulator for treatment of Multiple Sclerosis (MS) also inhibits lysosomal acid sphingomyelinase (ASMase). Treatment of cultured cells for 24 h with FTY720 (up to 10 μM) inhibited ASMase by >80% and this could be reversed by pre-treatment with the cathepsin protease inhibitor leupeptin (5 μM). In contrast, neutral sphingomyelinase activity was unaffected and sphingosine-1-phosphate treatment had no effect on ASMase. RT-PCR revealed no inhibition of ASMase mRNA and there was no direct (in vitro) inhibition of ASMase by either FTY720 or FTY720-phosphate. This suggests that its mechanism of inhibition is similar to that of tricyclic anti-depressants such as desipramine, which are also amphiphilic cationic drugs. Both Desipramine and FTY720 treatment reduced ASMase without significant inhibition of other lysosomal hydrolases but most hydrolases showed increased secretion (up to a 50% increase) providing more evidence of lysosomal disruption by these drugs.
Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA. dawg@uchicago.edu
Glyn
G
Dawson
Jingdong
J
Qin
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D002403:Cathepsins / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D000068876:Fingolimod Hydrochloride; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D011409:Propylene Glycols / Q000494:pharmacology*; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000929:Antidepressive Agents, Tricyclic; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007976:Leupeptins; D011409:Propylene Glycols; D006867:Hydrolases; D013108:Sphingomyelin Phosphodiesterase; D002403:Cathepsins; D000068876:Fingolimod Hydrochloride; C032854:leupeptin; D013110:Sphingosine; D003891:Desipramine