The influence of 1-beta-D-arabinofuranosylcytosine on the metabolism of phosphatidylcholine in human leukemic HL 60 and Raji cells.

ABSTRACT

We report that high-dose 1-beta-D-arabinofuranosylcytosine (Ara-C) treatment leads to substantial changes of membrane lipid composition in human leukemic cell lines. HL 60 cells are at least 10- to 20-fold more sensitive to Ara-C than Raji cells. After 4 h incubation with 50 microM Ara-C, both cells show deviations in their phosphatidylcholine (PC) and triglyceride (TG) contents, starting as early as 8 h after treatment. After 24 h, the Ara-C-induced changes in lipid metabolism are accompanied by a severe loss of viability in HL 60 cells but not in Raji cells. At this time point the HL 60 cells show a 20% depletion of PC with a concomitant increase in TG of 25%, whereas in Raji cells both PC and TG are increased 20 and 22%, respectively. The addition of lysophosphatidylcholine (lysoPC) antagonizes Ara-C-induced cell death in various leukemic cell lines and primary AML blasts from patients. Since lysoPC is a direct precursor for PC and increases the PC content of the membrane, we assume that the loss of PC in the sensitive cell line HL 60 and in other cells plays a role in Ara-C-induced toxicity. Further evidence for this mechanism is presented by the observation that hexadecylphosphocholine, an inhibitor of PC synthesis shows synergistic antiproliferative effects with Ara-C. We conclude that the rapid cell lysis described during high-dose Ara-C treatment seems to be mediated by reduction of cell membrane PC content.