Abstract:
:The function of acid ceramidase (ACDase), whose congenital deficiency leads to Farber disease, has been recognized to be vital to tumor cell biology, and inhibition of its activity may be beneficial in cancer therapy. Therefore, manipulation of the activity of this enzyme may have significant effect, especially on cancer cells. LCL521, Di-DMG-B13, is a lysosomotropic inhibitor of ACDase. Here we define complexities in the actions of LCL521 on ACDase. Systematic studies in MCF7 cells showed dose and time divergent action of LCL521 on ACDase protein expression and sphingolipid levels. Low dose of LCL521 (1 µM) effectively inhibited ACDase in cells, but the effects were transient. A higher dose of LCL521 (10 µM) caused a profound decrease of sphingosine and increase of ceramide, but additionally affected the processing and regeneration of the ACDase protein, with biphasic and reversible effects on the expression of ACDase, which paralleled the long term changes of cellular sphingosine and ceramide. Finally, the higher concentrations of LCL521 also inhibited Dihydroceramide desaturase (DES-1). In summary, LCL521 exhibits significant effects on ACDase in a dose and time dependent manner, but dose range and treatment time need to be paid attention to specify its future exploration on ACDase targeted cancer treatment.
journal_name
Bioorg Med Chemjournal_title
Bioorganic & medicinal chemistryauthors
Bai A,Bielawska A,Rahmaniyan M,Kraveka JM,Bielawski J,Hannun YAdoi
10.1016/j.bmc.2018.11.012subject
Has Abstractpub_date
2018-12-15 00:00:00pages
6067-6075issue
23-24eissn
0968-0896issn
1464-3391pii
S0968-0896(18)31452-4journal_volume
26pub_type
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