The Ether Lipid Inositol-C2-PAF is a Potent Inhibitor of Cell Proliferation in HaCaT Cells

• Published in: Chembiochem : a European journal of chemical biology Vol. 7; no. 3; pp. 441 - 449
• Main Authors: Fischer, Annette, Müller, Dieter, Zimmermann-Kordmann, Martin, Kleuser, Burkhard, Mickeleit, Michael, Laabs, Stephan, Löwe, Werner, Cantagrel, Frédéric, Reutter, Werner, Danker, Kerstin
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.03.2006; WILEY‐VCH Verlag
• Subjects: antiproliferative drug; antitumor agents; biological activity; Cell Differentiation - drug effects; Cell Line; Cell Proliferation - drug effects; Chromatography, Thin Layer; Humans; inositol; Inositol - analogs & derivatives; Inositol - pharmacology; Magnetic Resonance Spectroscopy; Mass Spectrometry; phospholipids; Platelet Activating Factor - analogs & derivatives; Platelet Activating Factor - pharmacology; Protein Precursors - metabolism; Transglutaminases - metabolism
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.200500336

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 (IC50=1.8 μM) and reduces the cytotoxicity relative to Glc‐PAF (LC50=15 μM). 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. Stopping cell growth: The synthesis and biological effects of the novel antiproliferative compound 1‐O‐octadecyl‐2‐O‐(2‐(myo‐inositolyl)‐ethyl)‐sn‐glycero‐3‐(R/S)‐phosphatidylcholine (Ino‐C2‐PAF, see structure) are reported here. In vitro, Ino‐C2‐PAF has a strong antiproliferative effect (IC50=1.8 μM) and a reduced cytotoxicity (LC50=15 μM) compared to related molecules.