Structure-dependent effects of glucose-containing analogs of platelet activating factor (PAF) on membrane integrity

Synthetic choline-containing phospholipids comprise a new class of compound s with antineoplastic properties. We have investigated the effect of recent ly synthesized glucose-containing analogs of lysophosphatidylcholine (glyce roglucophospholipid, Glc-PC) and of lysoplatelet activating factor (Glc-PAF ) and its C16, C14 and C12 derivatives (ET-16, ET-14, and ET-12) on prolife ration of immortalized human keratinocyte (HaCaT) cells. The data were comp ared to the ability of the compounds to intercalate into phosphatidylserine liposomes and to form lesions in planar bilayer membranes. A correlation b etween bioactivity and membrane activity was found. The number of molecules that intercalated into phosphatidylserine liposomes depended on the chemic al structure of the compounds and was in the order Glc-PAF approximate to E T-16 - ET-14 > Glc-PC > ET-12. All compounds induced membrane lesions, and the lesion forming activity was in the same order. Similar activity ranking s were found for the release of lactate dehydrogenase from HaCaT cells as a measure of lytic activity and for the influence on cell number as a measur e of proliferation. In the latter test, however, proliferation was already inhibited at nontoxic concentrations. From these findings, it may be conclu ded that the intercalation of the compounds at toxic concentrations leads t o the formation of membrane lesions and finally results in membrane rupture leading to cell death.