ALKYL LYSOPHOSPHOLIPIDS INHIBIT PHORBOL ESTER-STIMULATED PHOSPHOLIPASE-D ACTIVITY AND DNA-SYNTHESIS IN FIBROBLASTS

The antineoplastic alkyl lysophospholipids (ALP) -octadecyl-2-O-methyl -rac-glycero-3-phosphocholine (ET-18-OCH3) and 1-S-hexadecylthio-2-met hoxymethyl-2-deoxy- rac-glycero-3-phosphocholine (BM 41.440) were foun d to alter phospholipase D (PLD)-mediated phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn) hydrolysis in NIH3T3 fibroblast s. After a shorter (50 min) treatment, 2.5-7.5 mu g/ml concentrations of ALP stimulated PtdCho, but not PtdEtn, hgdrolysis 2-4-fold, At the same time, 7.5-25 mu g/ml concentrations of ALP significantly inhibite d the larger (5.8-6.5-fold) stimulatory effects of phorbol 12-myristat e 13-acetate (PMA) on both PtdCho and PtdEtn hydrolysis. When a brief (30 min) exposure of cells to 1-2.5 mu g/ml concentrations of BM 41.44 0 was followed by incubation of mashed cells for 3-16 h prior to the a ssay of PLD activity or DNA synthesis, the treated cells exhibited no increased PtdCho hydrolysis, while their responses to the stimulatory PMA effects on both PLD activity and DNA synthesis mere strongly reduc ed, The results suggest that the PLD and protein kinase C systems may be important cellular targets of ALP actions. (C) 1997 Federation of E uropean Biochemical Societies.