Differential effects of free and liposome-associated 1-O-octadecyl-2-O-methylglycerophosphocholine on protein kinase C.
Incorporation of ET-18-OCH3 into well-characterized liposomes known as ELL-12 has eliminated its gastrointestinal and hemolytic toxicity without loss of growth inhibiting activity. ET-18-OCH3, but not ELL-12, blunted the increase in membrane protein kinase C (PKC) activity induced by 12-O-tetradecanoylphorbol 13-myristate (TPA) and markedly reduced levels of PKC alpha in NIH 3T3 fibroblasts. Furthermore, prolonged treatment with ELL-12 neither inhibited TPA-induced translocations of PKC alpha and PKC delta to the particulate fraction nor caused down-regulation, and did not affect the cellular distribution of TPA-insensitive PKC zeta. In Jurkat T cells, where ELL-12 markedly induced apoptosis that was blocked by an inhibitor of caspase-3-like activities, it had no effect on PKC activity or translocation induced by TPA. Thus, it seems unlikely that PKC is involved in the therapeutic effects of ELL-12.
Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, DC 20007, USA. spiegel@bc.georgetown.edu
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Spiegel
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Olah
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Cuvillier
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Edsall
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Janoff
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019169:Jurkat Cells; D008081:Liposomes / Q000378:metabolism*; D051379:Mice; D010742:Phospholipid Ethers / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*
D008081:Liposomes; D010742:Phospholipid Ethers; C026659:edelfosine; D011493:Protein Kinase C