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 the HL-60 human myeloid leukemia cell line. Angelmicin B caused the dose-dependent inhibition of cell proliferation and induction of differentiation along the myelomonocytic pathway, as determined by morphological changes, nitroblue tetrazolium (NBT) reduction, and non-specific esterase and lysozyme activities at concentrations ranging from 0.1 to 0.5 microgram/ml. Also, it induced significantly the differentiation of mouse myeloid leukemia M1 cells. A similar concentration of angelmicin B inhibited the growth of the myeloid leukemia cell lines K562, HEL, KU812, ML-1, U937 and THP-1, but did not induce differentiation of these cells significantly. The differentiation of HL-60 cells was enhanced by combined treatment with angelmicin B and 1 alpha, 25-dihydroxyvitamin D3 (VD3), retinoic acid or tumor necrosis factor-alpha (TNF alpha). Angelmicin analogs (A1, A2, B, C and D) had almost equivalent effects on the differentiation of HL-60 cells, although angelmicins C and D inhibited src tyrosine kinase activity less than the other analogs. The effective concentrations of angelmicin B in src kinase inactivation was about 100-fold higher than those required for the growth inhibition and differentiation induction. These findings indicate that the differentiation-inducing activity of angelmicins is not associated with their src kinase-inhibiting activity, and may be associated with the modulation of other signal pathway(s).
Yokoyama
A
A
Department of Chemotherapy, Saitama Cancer Center Research Institute, Japan.
Okabe-Kado
J
J
Uehara
Y
Y
Oki
T
T
Tomoyasu
S
S
Tsuruoka
N
N
Honma
Y
Y
D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002762:Cholecalciferol / Q000494:pharmacology; D018922:HL-60 Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D009580:Nitroblue Tetrazolium; D009857:Oncogenes; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000880:Anthraquinones; D000903:Antibiotics, Antineoplastic; D014409:Tumor Necrosis Factor-alpha; C083655:angelmicin B; D002762:Cholecalciferol; D009580:Nitroblue Tetrazolium; D014212:Tretinoin; D011505:Protein-Tyrosine Kinases