J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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Originally published In Press as doi:10.1194/jlr.M500136-JLR200 on September 8, 2005

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Journal of Lipid Research, Vol. 46, 2315-2324, November 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

A lipid analogue that inhibits sphingomyelin hydrolysis and synthesis, increases ceramide, and leads to cell death

Peter I. Darroch*, Arie Dagan{dagger}, Tami Granot{dagger}, Xingxuan He*, Shimon Gatt{dagger} and Edward H. Schuchman1,*

* Department of Human Genetics, Mount Sinai School of Medicine, New York, NY 10029
{dagger} Department of Biochemistry, Hebrew University-Hadassah School of Medicine, Jerusalem 91120, Israel

Published, JLR Papers in Press, September 8, 2005. DOI 10.1194/jlr.M500136-JLR200

1 To whom correspondence should be addressed. e-mail: edward.schuchman{at}mssm.edu

We report the synthesis and characterization of a novel thiourea derivative of sphingomyelin (AD2765). In vitro assays using pure enzyme and/or cell extracts revealed that this compound inhibited the hydrolysis of BODIPY-conjugated or 14C-labeled sphingomyelin by acid sphingomyelinase and Mg2+-dependent neutral sphingomyelinase. Studies in normal human skin fibroblasts further revealed that AD2765 was taken up by cells and inhibited the hydrolysis of BODIPY-conjugated sphingomyelin in situ. In situ and in vitro studies also showed that this compound inhibited the synthesis of sphingomyelin from BODIPY-conjugated ceramide. The specificity of AD2765 for enzymes involved in sphingomyelin metabolism was demonstrated by the fact that it had no effect on the hydrolysis of BODIPY-conjugated ceramide by acid ceramidase or on the synthesis of BODIPY-conjugated glucosylceramide from BODIPY-conjugated ceramide. The overall effect of AD2765 on sphingomyelin metabolism was concentration-dependent, and treatment of normal human skin fibroblasts or cancer cells with this compound at concentrations > 10 µM led to an increase in cellular ceramide and cell death.

Thus, AD2765 might be used to manipulate sphingomyelin metabolism in various ways, potentially to reduce substrate accumulation in cells from types A and B Niemann-Pick disease patients, and/or to affect the growth of human cancer cells.

Abbreviations: ASM, acid sphingomyelinase; B12CER, BODIPY®-labeled C12-ceramide; B12SM, BODIPY®-labeled C12-sphingomyelin; DOPC, dioleoyl phosphatidylcholine; Ki, inhibition constant; LAMP-2, lysosomal-associated membrane protein-2; NPD, Niemann-Pick disease; SMPD-1, sphingomyelin phosphodiesterase-1

Supplementary key words sphingolipids • cancer • apoptosis


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