Differential regulation of phospholipase A(2) 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 A(2) (PLA(2)-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 (TNF alpha). Inhibition of purified secretory PLA(2) 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 PLA(2) activity in immature cells which cannot be explained by changes in membrane composition. Our data suggest that PLA(2) inhibition is most probably not the mechanism by which HePC mediates its antiproliferative effects. (C) 1997 Elsevier Science Inc.