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
- 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 lysosomalInhibition 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.…
MetadatenVerfasserangaben: | Eyad NaserGND, Stephanie Kadow, Fabian SchumacherORCiDGND, Zainelabdeen H. Mohamed, Christian KappeORCiDGND, Gabriele Hessler, Barbara PollmeierGND, Burkhard KleuserORCiDGND, Christoph Arenz, Katrin Anne BeckerORCiDGND, Erich GulbinsORCiDGND, Alexander CarpinteiroORCiDGND |
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URN: | urn:nbn:de:kobv:517-opus4-516635 |
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DOI: | https://doi.org/10.25932/publishup-51663 |
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ISSN: | 1866-8372 |
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Titel des übergeordneten Werks (Deutsch): | Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe |
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Untertitel (Englisch): | a direct and specific inhibitor of acid sphingomyelinase in vitro[S] |
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Schriftenreihe (Bandnummer): | Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe (1407) |
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Publikationstyp: | Postprint |
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Sprache: | Englisch |
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Datum der Erstveröffentlichung: | 04.01.2021 |
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Erscheinungsjahr: | 2021 |
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Veröffentlichende Institution: | Universität Potsdam |
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Datum der Freischaltung: | 14.03.2024 |
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Freies Schlagwort / Tag: | 1-aminodecylidene bis-phosphonic acid; acid ceramidase; bisphosphonates; cerami-des; enzymology; functional inhibitors of acid sphin-gomyelinase; lipid metabolism; lysosomal hydrolases; lysosome; sphingolipids; sphingomyelin |
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Ausgabe: | 6 |
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Seitenanzahl: | 17 |
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Quelle: | Journal of Lipid Research, Volume 61, Issue 6, 2020, Pages 896-910, ISSN 0022-2275, https://doi.org/10.1194/jlr.RA120000682 |
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Organisationseinheiten: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft |
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DDC-Klassifikation: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
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Peer Review: | Referiert |
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Publikationsweg: | Open Access / Green Open-Access |
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Lizenz (Deutsch): | CC-BY - Namensnennung 4.0 International |
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Externe Anmerkung: | Bibliographieeintrag der Originalveröffentlichung/Quelle |
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