Characterization of the small molecule ARC39, a direct and specific inhibitor of acid sphingomyelinase in vitro[S]
Inhibition of acid sphingomyelinase (ASM), a lysosomal enzyme that catalyzes the hydrolysis of sphingomyelin into ceramide and phosphorylcholine, may serve as an investigational tool or a therapeutic intervention to control many diseases. Specific ASM inhibitors are currently not sufficiently charac...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-06-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520436004 |
| _version_ | 1818690634451517440 |
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| author | Eyad Naser Stephanie Kadow Fabian Schumacher Zainelabdeen H. Mohamed Christian Kappe Gabriele Hessler Barbara Pollmeier Burkhard Kleuser Christoph Arenz Katrin Anne Becker Erich Gulbins Alexander Carpinteiro |
| author_facet | Eyad Naser Stephanie Kadow Fabian Schumacher Zainelabdeen H. Mohamed Christian Kappe Gabriele Hessler Barbara Pollmeier Burkhard Kleuser Christoph Arenz Katrin Anne Becker Erich Gulbins Alexander Carpinteiro |
| author_sort | Eyad Naser |
| collection | DOAJ |
| description | Inhibition of acid sphingomyelinase (ASM), a lysosomal enzyme that catalyzes the hydrolysis of sphingomyelin into ceramide and phosphorylcholine, may serve as an investigational tool or a therapeutic intervention to control many diseases. Specific ASM inhibitors are currently not sufficiently characterized. Here, we found that 1-aminodecylidene bis-phosphonic acid (ARC39) specifically and efficiently (>90%) inhibits both lysosomal and secretory ASM in vitro. Results from investigating sphingomyelin phosphodiesterase 1 (SMPD1/Smpd1) mRNA and ASM protein levels suggested that ARC39 directly inhibits ASM's catalytic activity in cultured cells, a mechanism that differs from that of functional inhibitors of ASM. We further provide evidence that ARC39 dose- and time-dependently inhibits lysosomal ASM in intact cells, and we show that ARC39 also reduces platelet- and ASM-promoted adhesion of tumor cells. The observed toxicity of ARC39 is low at concentrations relevant for ASM inhibition in vitro, and it does not strongly alter the lysosomal compartment or induce phospholipidosis in vitro. When applied intraperitoneally in vivo, even subtoxic high doses administered short-term induced sphingomyelin accumulation only locally in the peritoneal lavage without significant accumulation in plasma, liver, spleen, or brain. These findings require further investigation with other possible chemical modifications. In conclusion, our results indicate that ARC39 potently and selectively inhibits ASM in vitro and highlight the need for developing compounds that can reach tissue concentrations sufficient for ASM inhibition in vivo. |
| first_indexed | 2024-12-17T12:29:07Z |
| format | Article |
| id | doaj.art-5e9c3b6587c9418bb93a4e4217043165 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-17T12:29:07Z |
| publishDate | 2020-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-5e9c3b6587c9418bb93a4e42170431652022-12-21T21:48:41ZengElsevierJournal of Lipid Research0022-22752020-06-01616896910Characterization of the small molecule ARC39, a direct and specific inhibitor of acid sphingomyelinase in vitro[S]Eyad Naser0Stephanie Kadow1Fabian Schumacher2Zainelabdeen H. Mohamed3Christian Kappe4Gabriele Hessler5Barbara Pollmeier6Burkhard Kleuser7Christoph Arenz8Katrin Anne Becker9Erich Gulbins10Alexander Carpinteiro11Department of Molecular Biology, University of Duisburg-Essen, 45147 Essen, GermanyDepartment of Molecular Biology, University of Duisburg-Essen, 45147 Essen, GermanyDepartment of Molecular Biology, University of Duisburg-Essen, 45147 Essen, Germany; Department of Toxicology, Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, GermanyInstitute of Chemistry, Humboldt University of Berlin, 12489 Berlin, Germany; Medicinal Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, EgyptInstitute of Chemistry, Humboldt University of Berlin, 12489 Berlin, GermanyDepartment of Molecular Biology, University of Duisburg-Essen, 45147 Essen, GermanyDepartment of Molecular Biology, University of Duisburg-Essen, 45147 Essen, GermanyDepartment of Toxicology, Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, GermanyInstitute of Chemistry, Humboldt University of Berlin, 12489 Berlin, GermanyDepartment of Molecular Biology, University of Duisburg-Essen, 45147 Essen, GermanyDepartment of Molecular Biology, University of Duisburg-Essen, 45147 Essen, Germany; Department of Surgery, University of Cincinnati, Cincinnati, OH 45229Department of Molecular Biology, University of Duisburg-Essen, 45147 Essen, Germany; Department of Hematology, University Hospital Essen, 45147 Essen, Germany; To whom correspondence should be addressedInhibition of acid sphingomyelinase (ASM), a lysosomal enzyme that catalyzes the hydrolysis of sphingomyelin into ceramide and phosphorylcholine, may serve as an investigational tool or a therapeutic intervention to control many diseases. Specific ASM inhibitors are currently not sufficiently characterized. Here, we found that 1-aminodecylidene bis-phosphonic acid (ARC39) specifically and efficiently (>90%) inhibits both lysosomal and secretory ASM in vitro. Results from investigating sphingomyelin phosphodiesterase 1 (SMPD1/Smpd1) mRNA and ASM protein levels suggested that ARC39 directly inhibits ASM's catalytic activity in cultured cells, a mechanism that differs from that of functional inhibitors of ASM. We further provide evidence that ARC39 dose- and time-dependently inhibits lysosomal ASM in intact cells, and we show that ARC39 also reduces platelet- and ASM-promoted adhesion of tumor cells. The observed toxicity of ARC39 is low at concentrations relevant for ASM inhibition in vitro, and it does not strongly alter the lysosomal compartment or induce phospholipidosis in vitro. When applied intraperitoneally in vivo, even subtoxic high doses administered short-term induced sphingomyelin accumulation only locally in the peritoneal lavage without significant accumulation in plasma, liver, spleen, or brain. These findings require further investigation with other possible chemical modifications. In conclusion, our results indicate that ARC39 potently and selectively inhibits ASM in vitro and highlight the need for developing compounds that can reach tissue concentrations sufficient for ASM inhibition in vivo.http://www.sciencedirect.com/science/article/pii/S0022227520436004sphingolipidssphingomyelinceramideslipid metabolismenzymologylysosome |
| spellingShingle | Eyad Naser Stephanie Kadow Fabian Schumacher Zainelabdeen H. Mohamed Christian Kappe Gabriele Hessler Barbara Pollmeier Burkhard Kleuser Christoph Arenz Katrin Anne Becker Erich Gulbins Alexander Carpinteiro Characterization of the small molecule ARC39, a direct and specific inhibitor of acid sphingomyelinase in vitro[S] Journal of Lipid Research sphingolipids sphingomyelin ceramides lipid metabolism enzymology lysosome |
| title | Characterization of the small molecule ARC39, a direct and specific inhibitor of acid sphingomyelinase in vitro[S] |
| title_full | Characterization of the small molecule ARC39, a direct and specific inhibitor of acid sphingomyelinase in vitro[S] |
| title_fullStr | Characterization of the small molecule ARC39, a direct and specific inhibitor of acid sphingomyelinase in vitro[S] |
| title_full_unstemmed | Characterization of the small molecule ARC39, a direct and specific inhibitor of acid sphingomyelinase in vitro[S] |
| title_short | Characterization of the small molecule ARC39, a direct and specific inhibitor of acid sphingomyelinase in vitro[S] |
| title_sort | characterization of the small molecule arc39 a direct and specific inhibitor of acid sphingomyelinase in vitro s |
| topic | sphingolipids sphingomyelin ceramides lipid metabolism enzymology lysosome |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520436004 |
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