Induction of morphological and functional differentiation of human myeloid leukemia cells (HL-60 and LK) by a benzoic acid derivative of retinoic acid

Abstract

In previous studies we have shown that the synthetic retinoid (E)-4[2–5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl-1-propenylbenzoic acid (TTNPB) stimulates the growth of myeloid progenitors from normal and myelodysplastic patients. In the present study we compared TTNPB with 13- cis-retinoic acid (RA) in its potential to inhibit cell growth and to induce morphological differentiation and functional activity in two cell lines established in vitro from either acute promyelocytic (HL-60) or acute myelomonocytic (LK) patients. Both agents, 10 −6 M, were found to effectively inhibit cell growth and cause a significant decrease in number of immature granulocytes in both cell lines. However, while in HL-60 cells this decrease was associated with a concomitant increase in fully mature granulocytes (neutrophil-like cells) the maturation of LK cells was blocked at the metamyelocyte stage. Study of the functional activity of the induced cells revealed that the rate of superoxide (O 2 −) production, as assayed by superoxide dismutase-inhibitable ferricytochrome c reduction, was faster in RA treated HL-60 cells than in TTNPB treated cells (0.41 vs 0.25 nmol. O 2 −/10 6 cells/60 min). Superoxide production by LK cells treated by either TTNPB or RA was negligible. The percentage of O 2 −-producing cells was determined cytochemically by their ability to reduce the dye nitroblue tetrazolium (NBT). The results showed that production of O 2 − by LK cells exposed to TTNPB or RA was negligible by this method as well. A higher percentage of HL-60 cells reduced NBT following incubation with RA than with TTNPB (93 ± 4% vs 26 ± 2%), but neither of the two retinoids affected the ability of LK cells to reduce NBT. TTNPB thus proved less effective than RA in inducing morphological and functional differentiation in HL-60 cells, whereas in LK cells both agents inhibited cell growth but induced only partial cell differentiation.