The ether lipid inositol-C2-PAF is a potent inhibitor of cell proliferation in HaCaT cells.
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 alpha-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-alpha-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 alpha-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 microM) and reduces the cytotoxicity relative to Glc-PAF (LC(50)=15 microM). 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.
Fischer
Annette
A
Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Institut für Biochemie und Molekularbiologie, Arnimallee 22, 14195 Berlin-Dahlem, Germany.
Müller
Dieter
D
Zimmermann-Kordmann
Martin
M
Kleuser
Burkhard
B
Mickeleit
Michael
M
Laabs
Stephan
S
Löwe
Werner
W
Cantagrel
Frédéric
F
Reutter
Werner
W
Danker
Kerstin
K
D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002855:Chromatography, Thin Layer; D006801:Humans; D007294:Inositol / Q000031:analogs & derivatives* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010972:Platelet Activating Factor / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011498:Protein Precursors / Q000378:metabolism; D011503:Transglutaminases / Q000378:metabolism
C587359:1-O-octadecyl-2-O-(2-inositolylethyl)-glycero-3-phosphatidylcholine; D010972:Platelet Activating Factor; D011498:Protein Precursors; D007294:Inositol; C032253:involucrin; D011503:Transglutaminases