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Induction of ceramide-mediated apoptosis by the anticancer pPhospholipid analog, hexadecylphosphocholine

Item Type:Article
Title:Induction of ceramide-mediated apoptosis by the anticancer pPhospholipid analog, hexadecylphosphocholine
Creators Name:Wieder, T. and Orfanos, C.E. and Geilen, C.C.
Abstract:The prototype of a new class of antiproliferative phospholipid analogs, hexadecylphosphocholine (HePC), has been shown to inhibit tumor growth and is currently used for the treatment of cutaneous metastases of mammary carcinomas. Although several cellular targets of HePC, e.g. protein kinase C and CTP:phosphocholine cytidylyltransferase, have been proposed, the mechanisms of HePC-induced anticancer activity are still unclear. Considering that the antiproliferative effect of HePC correlates with inhibition of phosphatidylcholine biosynthesis, which is tightly coupled to sphingomyelin biosynthesis, we tested the hypothesis that treatment of cells with the anticancer drug leads to increased cellular ceramide and subsequently to apoptotic cell death. In the present study, we showed that 25 micromol/liter HePC induced apoptosis. In further experiments, we demonstrated that HePC inhibited the incorporation of radiolabeled choline into phosphatidylcholine and at a later time point into sphingomyelin. This was confirmed by metabolic labeling of the lipid backbone using radiolabeled serine, and it was shown that HePC decreased the incorporation of serine into sphingomyelin by 35% and simultaneously increased the incorporation of serine into ceramide by 70%. Determination of the amount of ceramide revealed an increase of 53% in HePC-treated cells compared with controls. In accordance with the hypothesis that elevated ceramide levels may be the missing link between the metabolic effects of HePC and its proapoptotic properties, HePC-induced apoptosis was blocked by fumonisin B1, an inhibitor of ceramide synthesis. Furthermore, we found that membrane-permeable ceramides additively increased the apoptotic effect of HePC.
Keywords:Antineoplastic Agents, Apoptosis, Carboxylic Acids, Cell Division, Cell Line, Ceramides, Fumonisins, Phosphatidylcholines, Phosphorylcholine, Sphingomyelins
Source:Journal of Biological Chemistry
Publisher:American Society for Biochemistry and Molecular Biology
Page Range:11025-11031
Date:1 May 1998
Official Publication:https://doi.org/10.1074/jbc.273.18.11025
PubMed:View item in PubMed

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