Differential regulation of phospholipase A2 in human leukemia cells by the etherphospholipid analogue hexadecylphosphocholine.
Hexadecylphosphocholine (HePC) is the main representative of a new group of antineoplastic agents, the alkylphosphocholines, which were originally derived from cytotoxic etherlysophospholipids. HePC shows antiproliferative action against a whole variety of tumor cells and tumors in vitro and in vivo. Furthermore, it also induces differentiation in some hematologic cell lines and prevents invasive growth of neoplastic cells in vitro. To date, the precise molecular mechanisms mediating the biological effects of HePC have not been identified yet. As etherlysophospholipids seem to inhibit some pathways of lipid-dependent intracellular signalling, similar effects may be relevant for HePC. We therefore investigated the influence of HePC on phospholipase A2 (PLA2-EC 3.1.1) in the human leukemia cell line U 937. HePC seems to inhibit enzyme activity independently of protein kinase C (PKC) in differentiated U 937 cells stimulated by tumor necrosis factor alpha (TNFalpha). Inhibition of purified secretory PLA2 from snake venom (EC 3.1.1.4) in vitro shows characteristics of a non-competitive mode. In contrast, HePC leads to an enhancement of PLA2 activity in immature cells which cannot be explained by changes in membrane composition. Our data suggest that PLA, inhibition is most probably not the mechanism by which HePC mediates its antiproliferative effects.
Berkovic
D
D
Department of Hematology and Oncology at the University Clinic of Gottingen, Germany.
Lüders
S
S
Goeckenjan
M
M
Hiddemann
W
W
Fleer
E A
EA
D000215:Acylation; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation; D002455:Cell Division; D002470:Cell Survival / Q000187:drug effects; D004351:Drug Resistance; D004789:Enzyme Activation; D006801:Humans; D010741:Phospholipases A / Q000302:isolation & purification / Q000378:metabolism*; D054467:Phospholipases A2; D010743:Phospholipids / Q000032:analysis; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000970:Antineoplastic Agents; D010743:Phospholipids; D014409:Tumor Necrosis Factor-alpha; D010767:Phosphorylcholine; C039128:miltefosine; D011493:Protein Kinase C; D010741:Phospholipases A; D054467:Phospholipases A2