Inhibition of glycoprotein biosynthesis by the inducers of HL-60 cell differentiation, aclacinomycin A and marcellomycin

The trisaccharide-containing anthracyclines aclacinomycin A (ACM) and marcellomycin (MCM) have been shown by our laboratory to be potent inducers of HL-60 leukemia cell maturation, while the monosaccharide-containing anthracyclines Adriamycin and pyrromycin were inactive and significantly less potent, respectively, as initiators of the differentiation of these malignant cells. We have now observed that ACM and MCM are potent inhibitors of both total glycoprotein synthesis and the formation of lipid-linked oligosaccharide intermediates in intact HL-60 cells. This inhibitory activity was both concentration and time dependent and was maximal after 12 hr exposure to 30 nM ACM or MCM, conditions under which both cell growth and total protein synthesis were maintained at levels equal to those of untreated cells. In contrast, exposure of HL-60 cells to pyrromycin or Adriamycin, even at cytotoxic concentrations, did not result in specific decreases in the synthesis of glycoproteins containing asparagine-linked oligosaccharides. Maximum inhibition of the formation of lipid-linked intermediates by ACM or MCM preceded the loss of cell surface transferrin-binding activity (maximal at 24 hr), which in turn preceded the minimal exposure time necessary for significant induction of differentiation by either of the active anthracyclines (36 hr). These findings demonstrate a new biochemical site of action for ACM and MCM and suggest that this activity is involved in the induction of terminal differentiation of HL-60 leukemia cells by these antitumor agents.