ANGELMICIN-B, A NEW INHIBITOR OF ONCOGENIC SIGNAL-TRANSDUCTION, INHIBITS GROWTH AND INDUCES MYELOMONOCYTIC DIFFERENTIATION OF HUMAN MYELOID-LEUKEMIA HL-60 CELLS

Angelmicin B is a new Microbial substance which inhibits src tyrosine kinase activity and oncogenic signal transduction. We investigated the effect of angelmicin B on the proliferation and differentiation of th e HL-60 human myeloid leukemia cell line. Angelmicin B caused the dose -dependent inhibition of cell proliferation and induction of different iation along the myelomonocytic pathway, as determined by morphologica l changes, nitroblue tetrazolium (NET) reduction, and non-specific est erase and lysozyme activities at concentrations ranging from 0.1 to 0. 5 mu g/ml. Also, it induced significantly the differentiation of mouse myeloid leukemia M1 cells. A similar concentration of angelmicin B in hibited the growth of the myeloid leukemia cell lines K562, HEL, KU812 , ML-1, U937 and THP-1, but did not induce differentiation of these ce lls significantly. The differentiation of HL-60 cells was enhanced by combined treatment with angelmicin B and 1 alpha,25-dihydroxyvitamin D -3 (VD3), retinoic acid or tumor necrosis factor-alpha (TNF alpha). An gelmicin analogs (A1,A2, B, C and D) had almost equivalent effects on the differentiation of HL-60 cells, although angelmicins C and D inhib ited src tyrosine kinase activity less than the other analogs. The eff ective concentrations of angelmicin B in src kinase inactivation was a bout 100-fold higher than those required for the growth inhibition and differentiation induction. These findings indicate that the different iation-inducing activity of angelmicins is not associated with their s rc kinase-inhibiting activity, and may be associated with the modulati on of other signal pathway(s). Copyright (C) 1996 Elsevier Science Ltd .