Structure-dependent effects of glucose-containing analogs of platelet activating factor (PAF) on membrane integrity.
Synthetic choline-containing phospholipids comprise a new class of compounds with antineoplastic properties. We have investigated the effect of recently synthesized glucose-containing analogs of lysophosphatidylcholine (glyceroglucophospholipid, Glc-PC) and of lysoplatelet activating factor (Glc-PAF) and its C16, C14 and C12 derivatives (ET-16, ET-14, and ET-12) on proliferation of immortalized human keratinocyte (HaCaT) cells. The data were compared to the ability of the compounds to intercalate into phosphatidylserine liposomes and to form lesions in planar bilayer membranes. A correlation between bioactivity and membrane activity was found. The number of molecules that intercalated into phosphatidylserine liposomes depended on the chemical structure of the compounds and was in the order Glc-PAF approximately ET-16 approximately ET-14 > Glc-PC > ET-12. All compounds induced membrane lesions, and the lesion forming activity was in the same order. Similar activity rankings 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 measure of proliferation. In the latter test, however, proliferation was already inhibited at non-toxic concentrations. From these findings, it may be concluded that the intercalation of the compounds at toxic concentrations leads to the formation of membrane lesions and finally results in membrane rupture leading to cell death.
Wiese
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Research Center Borstel, Center for Medicine and Biosciences, Department of Immunochemistry and Biochemical Microbiology, Germany.
Wieder
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Mickeleit
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Reinöhl
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Geilen
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CC
Seydel
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Reutter
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D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004553:Electric Conductivity; D004735:Energy Transfer; D005947:Glucose / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008081:Liposomes / Q000737:chemistry / Q000187:drug effects* / Q000648:ultrastructure*; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D010539:Permeability / Q000187:drug effects; D010713:Phosphatidylcholines / Q000737:chemistry / Q000378:metabolism; D010715:Phosphatidylglycerols / Q000378:metabolism; D010718:Phosphatidylserines / Q000737:chemistry / Q000378:metabolism; D010972:Platelet Activating Factor / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship
D008081:Liposomes; D008563:Membrane Lipids; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; D010718:Phosphatidylserines; D010972:Platelet Activating Factor; D005947:Glucose