Structure-activity relationship between anthracycline-induced differentiation and inhibition of glycoprotein...

The effect of adriamycin, daunomycin, N,N-dimethyladriamycin, N,N-dimethyldaunomycin, pyrromycin, marcellomycin, and aclacinomycin A on erythroid differentiation and glycoprotein synthesis in Friend erythroleukemia cells, clone F4-6 was investigated. Whereas N-dimethylated natural anthracyclines, pyrromycin, marcellomycin, and aclacinomycin A stimulated erythroid differentiation (induction of hemoglobin synthesis), this was not seen with adriamycin, daunomycin and their N-dimethylated derivatives. The incorporation of 3H-mannose in glycoprotein was inhibited by the N-alkylated natural anthracyclines at a concentration at which they induced erythroid differentiation. N,N-Dimethyladriamycin and N,N-dimethyldaunomycin only inhibited 3H-mannose incorporation into glycoprotein at cytotoxic concentrations. However, adriamycin and daunomycin did not inhibit glycoprotein synthesis, even at high cytotoxic concentrations. Aclacinomycin A decreased the incorporation of 3H-mannose into proteins earlier than the incorporation into dolichol-linked oligosaccharide intermediates. Tunicamycin, a specific inhibitor of glycoprotein synthesis, failed to stimulate differentiation in Friend erythroleukemia cells. These results indicate a structure-specific induction of the differentiation and inhibition of glycoprotein synthesis in Friend cells by N-alkylated anthracyclines. The inhibition of glycoprotein synthesis may be involved in the induction of differentiation by N-alkylated anthracyclines, but it cannot be the only target for the differentiation-inducing effect of these substances.