Effects of Synthetic Sphingosine-1-Phosphate Analogs on Cytosolic Phospholipase A2α–Independent Release of Arachidonic Acid and Cell Toxicity in L929 Fibrosarcoma Cells: the Structure–Activity Relationship
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概要
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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 α cytosolic phospholipase A2 (cPLA2α)] and L929-cPLAα–siRNA cells (L929 cells treated with small interference RNA for cPLA2α). Treatment with pharmacological inhibitors of secretory and Ca2+-independent PLA2s 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 PLA2 activity and its toxicity in cells. [Supplementary Fig. 1: available only at http://dx.doi.org/10.1254/jphs.08284FP]
著者
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SHIMIZU Masaya
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University
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MURAMATSU Yuki
Laboratory of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University
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TADA Eiko
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University
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KUROSAWA Takeshi
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University
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YAMAURA Erika
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University
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NAKAMURA Hiroyuki
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University
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FUJINO Hiromichi
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University
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HOUJYO Yuuya
Laboratory of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University
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MIYASAKA Yuri
Laboratory of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University
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KOIDE Yuuki
Laboratory of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University
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NISHIDA Atsushi
Laboratory of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University
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MURAYAMA Toshihiko
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University
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Tada Eiko
Laboratory Of Chemical Pharmacology Graduate School Of Pharmaceutical Sciences Chiba University
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Koide Yuuki
Laboratory Of Organic Chemistry Graduate School Of Pharmaceutical Sciences Chiba University
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Houjyo Yuuya
Laboratory Of Organic Chemistry Graduate School Of Pharmaceutical Sciences Chiba University
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Yamaura Erika
Laboratory Of Chemical Pharmacology Graduate School Of Pharmaceutical Sciences Chiba University
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Miyasaka Yuri
Laboratory Of Organic Chemistry Graduate School Of Pharmaceutical Sciences Chiba University
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Muramatsu Yuki
Laboratory Of Organic Chemistry Graduate School Of Pharmaceutical Sciences Chiba University
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Shimizu Masaya
Laboratory Of Chemical Pharmacology Graduate School Of Pharmaceutical Sciences Chiba University
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Kurosawa Takeshi
Laboratory Of Chemical Pharmacology Graduate School Of Pharmaceutical Sciences Chiba University
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Fujino Hiromichi
Laboratory Of Chemical Pharmacology Graduate School Of Pharmaceutical Sciences Chiba University
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Murayama Toshihiko
Laboratory Of Chemical Pharamacology Graduate School Of Pharmaceutical Sciences Chiba University
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Matsuzawa Yasuo
Department Of Internal Medicine Toho University School Of Medicine Sakura Hospital
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Nishida Atsushi
Laboratory Of Organic Chemistry Graduate School Of Pharmaceutical Sciences Chiba University
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Nakamura Hiroyuki
Laboratory Of Chemical Pharmacology Graduate School Of Pharmaceutical Sciences Chiba University
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Nakamura Hiroyuki
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
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Koide Yuuki
Laboratory of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
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Kurosawa Takeshi
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
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Miyasaka Yuri
Laboratory of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
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Fujino Hiromichi
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
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Muramatsu Yuki
Laboratory of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
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Houjyo Yuuya
Laboratory of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
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Yamaura Erika
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
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Tada Eiko
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
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