Hexadecylphosphocholine inhibits phosphatidylinositol and phosphatidylcholine phospholipase C in human leukemia cells.
Hexadecylphosphocholine (HePC) is the main representative of a new group of antineoplastic agents, the alkylphosphocholines. Besides remarkable antiproliferative properties on tumor cells in vitro and in vivo, HePC also induces differentiation and inhibits invasive growth of neoplastic cells. Knowledge of the molecular mechanisms by which HePC mediates its biological effects is poor. The observation that analogous substances, the alkyllysophospholipids, may interfere with lipid dependent intracellular signaling suggested similar mechanisms for HePC. We therefore investigated the effects of HePC on phospholipase C (PLC) activation in intact human leukemia cell lines. HePC inhibited fMLP induced phosphatidylinositol-specific PLC activation in HL60 cells and TNF-alpha induced activation of phosphatidylcholine-specific PLC in U937 cells. HePC reduced the number of TNF-alpha receptors on the surface of U937 cells by about 60%. Receptors for fMLP were not affected. Inhibition of TNF-alpha induced PC-PLC activation, however, seemed to be regulated at a post-receptor level as PLC inhibition and receptor occupancy did not correlate.
Berkovic
D
D
Department of Hematology and Oncology, University Clinic of Göttingen, Germany.
Goeckenjan
M
M
Lüders
S
S
Hiddemann
W
W
Fleer
E A
EA
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002855:Chromatography, Thin Layer; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000201:enzymology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D014409:Tumor Necrosis Factor-alpha; D010767:Phosphorylcholine; C039128:miltefosine; D009240:N-Formylmethionine Leucyl-Phenylalanine; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C; D043265:Phosphatidylinositol Diacylglycerol-Lyase