| Effects of synthetic sphingosine-1-phosphate analogs on cytosolic phospholipase A2alpha-independent release of arachidonic acid and cell toxicity in L929 fibrosarcoma cells: the structure-activity relationship. | |
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MedLine Citation:
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PMID: 19276615 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Sphingolipid metabolites including ceramide, sphingosine, and their phosphorylated products [sphingosine-1-phosphate (S1P) and ceramide-1-phosphate] regulate cell functions including arachidonic acid (AA) metabolism and cell death. The development of analogs of S1P may be useful for regulating these mediator-induced cellular responses. We synthesized new analogs of S1P and examined their effects on the release of AA and cell death in L929 mouse fibrosarcoma cells. Among the analogs tested, several compounds including DMB-mC11S [dimethyl (2S,3R)-2-tert-butoxycarbonylamino-3-hydroxy-3-(3'-undecyl)phenylpropyl phosphate] and DMB-mC9S [dimethyl (2S,3R)-2-tert-butoxycarbonylamino-3-hydroxy-3-(3'-nonyl)phenylpropyl phosphate] released AA within 1 h and caused cell death 6 h after treatment. The release of AA was observed in C12 cells [a L929 variant lacking a type alpha cytosolic phospholipase A(2) (cPLA(2)alpha)] and L929-cPLAalpha-siRNA cells (L929 cells treated with small interference RNA for cPLA(2)alpha). Treatment with pharmacological inhibitors of secretory and Ca(2+)-independent PLA(2)s decreased the DMB-mC11S-induced release of AA. The effect of the S1P analogs tested on the release of AA was comparable to that on cell death in L929 cells, and a high correlation coefficient was observed. Two analogs lacking a butoxycarbonyl moiety [DMAc-mC11S (dimethyl (2S,3R)-2-acetamino-3-hydroxy-3-(3'-undecyl)phenylpropyl phosphate] and DMAm-mC11S [dimethyl (2S,3R)-2-amino-3-hydroxy-3-(3'-undecyl)phenylpropyl phosphate)] had inhibitory effects on the release of AA and cell toxicity induced by DMB-mC11S. Synthetic phosphorylated lipid analogs may be useful for studying PLA(2) activity and its toxicity in cells. [Supplementary Fig. 1: available only at http://dx.doi.org/10.1254/jphs.08284FP]. |
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Authors:
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Masaya Shimizu; Yuki Muramatsu; Eiko Tada; Takeshi Kurosawa; Erika Yamaura; Hiroyuki Nakamura; Hiromichi Fujino; Yuuya Houjyo; Yuri Miyasaka; Yuuki Koide; Atsushi Nishida; Toshihiko Murayama |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-03-11 |
Journal Detail:
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Title: Journal of pharmacological sciences Volume: 109 ISSN: 1347-8613 ISO Abbreviation: J. Pharmacol. Sci. Publication Date: 2009 Mar |
Date Detail:
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Created Date: 2009-03-23 Completed Date: 2009-05-26 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101167001 Medline TA: J Pharmacol Sci Country: Japan |
Other Details:
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Languages: eng Pagination: 431-43 Citation Subset: IM |
Affiliation:
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Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Arachidonic Acid / metabolism* Cell Death / drug effects Cell Line, Tumor Fibrosarcoma / metabolism Group IV Phospholipases A2 / drug effects*, metabolism Lysophospholipids / chemical synthesis, chemistry, pharmacology* Mice RNA, Small Interfering / metabolism Sphingosine / analogs & derivatives*, chemical synthesis, chemistry, pharmacology Structure-Activity Relationship Time Factors |
| Chemical | |
Reg. No./Substance:
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0/Lysophospholipids; 0/RNA, Small Interfering; 123-78-4/Sphingosine; 26993-30-6/sphingosine 1-phosphate; 506-32-1/Arachidonic Acid; EC 3.1.1.4/Group IV Phospholipases A2 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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