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The Ether Lipid Inositol‐C2‐PAF is a Potent Inhibitor of Cell Proliferation in HaCaT Cells
Author(s) -
Fischer Annette,
Müller Dieter,
ZimmermannKordmann Martin,
Kleuser Burkhard,
Mickeleit Michael,
Laabs Stephan,
Löwe Werner,
Cantagrel Frédéric,
Reutter Werner,
Danker Kerstin
Publication year - 2006
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200500336
Subject(s) - hacat , chemistry , biochemistry , cell growth , phosphatidylcholine , keratinocyte , cytotoxicity , phospholipid , in vitro , membrane
The search for specific anticancer drugs that do not interfere with DNA synthesis or influence the cytoskeleton has led to the development of modified phospholipids with antiproliferative properties. These compounds cause remodeling of the structure and function of plasma membranes. Recently, we described novel compounds, the glycosidated phospholipids, that surprisingly inhibit cell proliferation. These compounds contain α‐ D ‐glucose in the sn ‐2 position of the glycerol backbone of phosphatidylcholine (PC) and platelet‐activating factor (PAF), which gives rise to 2‐glucophosphatidylcholine (Glc‐PC) and 1‐ O ‐octadecyl‐2‐ O ‐α‐ d‐ glucopyranosyl‐ sn ‐2‐glycero‐3‐phosphatidylcholine (Glc‐PAF), respectively. Glc‐PC and Glc‐PAF inhibit the growth of HaCaT cells at nontoxic concentrations. Here we report the introduction of myo ‐inositol, in place of α‐ D ‐glucose, in the sn ‐2 position of the glycerol backbone; this leads to two diastereomeric 1‐ O ‐octadecyl‐2‐ O ‐(2‐( myo ‐inositolyl)‐ethyl)‐ sn ‐glycero‐3‐( R/S )‐phosphatidylcholines (Ino‐C2‐PAF). The inositol‐containing PAF enhances the antiproliferative capacity (IC 50 =1.8 μ M ) and reduces the cytotoxicity relative to Glc‐PAF (LC 50 =15 μ M ). Through biological assays, we showed that, in HaCaT cells, Ino‐C2‐PAF causes upregulation of the keratinocyte‐specific differentiation marker involucrin, increases the activity of the differentiation marker transglutaminase, and induces apoptosis at nontoxic concentrations. Ino‐C2‐PAF therefore seems to be a promising candidate for development as an antiproliferative drug for the treatment of hyperproliferative diseases of the skin.