Inhibition of the synthesis of glycoproteins and induction of the differentiation of HL-60 promyelocytic leukemia cells by 6-methylmercaptopurine ribonucleoside.
HL-60 promyelocytic leukemia cells were induced to differentiate along the granulocytic pathway by exposure to 6-methylmercaptopurine ribonucleoside (6-MMPR). The interference with cellular replication and the induction of terminal maturation by 6-MMPR appeared to be a consequence of the inhibition of purine nucleotide biosynthesis de novo, since the simultaneous exposure of HL-60 cells to 6-MMPR and adenine completely prevented cellular differentiation, as measured by both nitro-blue tetrazolium reduction and the phagocytosis of latex beads, and partially prevented growth inhibition. The induction of HL-60 leukemia cell maturation by 6-MMPR was preceded by a marked reduction in the incorporation of [3H]mannose into glycoproteins and into the dolichol-oligosaccharide precursors of N-linked glycoprotein biosynthesis. Simultaneous exposure of HL-60 cells to 6-MMPR and adenine completely prevented the reduction in [3H]mannose incorporation into glycoproteins produced by the purine nucleoside antimetabolite. These findings suggest that the utilization of mannose for glycoprotein biosynthesis may be a component of the mechanism by which 6-MMPR causes the induction of the terminal differentiation of HL-60 leukemia cells.
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D006023:Glycoproteins / Q000096:biosynthesis*; D006801:Humans; D007288:Inosine / Q000031:analogs & derivatives*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008358:Mannose / Q000378:metabolism; D008778:Methylthioinosine / Q000627:therapeutic use*
D000964:Antimetabolites, Antineoplastic; D006023:Glycoproteins; D008778:Methylthioinosine; D007288:Inosine; D008358:Mannose