EFFECT OF N-3 AND N-6 FATTY-ACIDS ON PROLIFERATION AND DIFFERENTIATION OF PROMYELOCYTIC LEUKEMIC HL-60 CELLS

Promyelocytic leukemic HL-60 cells were incubated with different fatty acids. Arachidonic acid (AA; 20:4, n-6) and eicosapentaenoic acid (EP A; 20:5, n-3) were the most potent inhibitors of proliferation in a do se-dependent way. Retinoic acid (RA) was used as a positive control. I nhibitors of cyclooxygenase and lipoxygenase or addition of antioxidan ts did not influence the effect of EPA or AA on cell proliferation Inc reased capacity to generate superoxide anions after phorbol ester trea tment and a reduced serglycin messenger RNA level in cells treated wit h AA or EPA indicated that these fatty acids induced differentiation i n HL-60 cells similar to that induced by RA. However, down-regulation of the c-myc mRNA level, also typical for differentiation with RA in H L-60 cells. was not observed in cells incubated with AA or EPA. Flow c ytometric analyses showed that in cultures incubated with AA or EPA, t he proportion of cells in the G(1) phase of the cell cycle increased. Similar effects were observed with RA. By flow cytometry and light sca tter analyses it could be shown that AA made 8% of the cells apoptotic and 7% necrotic. The corresponding numbers were 21% and 10% for RA-tr eated cells, and 19% and 32% for EPA-treated cells. The present study shows that AA and EPA reduce the proliferation rate of HL-60 cells. Th is is mediated by mechanisms independent of eicosanoids or lipid perox idation products and is due to effects both on apoptosis/necrosis and cell differentiation. (C) 1994 by The American Society of Hematology.