Induction of erythroid differentiation in K562 cells by inhibitors of inosine monophosphate dehydrogenase.
The effects of three inhibitors of inosine monophosphate (IMP) dehydrogenase on a human erythroleukemic cell line, K562, were studied. Following incubation with these inhibitors, K562 cells underwent differentiation and accumulated hemoglobins. The induction of hemoglobin accumulation was dose dependent; maximum induction was observed at 100, 25, and 3 microM, respectively, for ribavirin, tiazofurin, and mycophenolic acid. The induction was associated with reduction of intracellular GTP content and was blocked by adding guanosine within 24 h after adding inducer. The effective dose for half-maximum induction by ribavirin was 3 times less than that for 50% inhibition of K562 proliferation; however, for tiazofurin and mycophenolic acid, it closely approximated the concentrations which suppressed cellular proliferation. Ribavirin was sequestered preferentially inside the K562 cells, and the induction by ribavirin had a greater than 30-fold increase in hemoglobin. Studies with isoelectric focusing, globin chain analyses, and immunochemical assays indicated that both A gamma and G gamma were detected and that the hemoglobin produced in the ribavirin-treated cells consisted of approximately 60% fetal hemoglobin and its acetylated equivalents. The adult-type alpha globin was found, while no beta globin chains were demonstrated. Thus, accumulation of fetal hemoglobin and production of alpha globin chain in ribavirin-treated cells are different from the pattern of hemoglobins induced by hemin.
Yu
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Department of Molecular and Experimental Medicine, Research Institute of Scripps Clinic, La Jolla, California 92037.
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D002451:Cell Compartmentation; D002455:Cell Division / Q000187:drug effects; D004920:Erythropoiesis / Q000187:drug effects*; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D007658:Ketone Oxidoreductases / Q000037:antagonists & inhibitors*; D004915:Leukemia, Erythroblastic, Acute; D009173:Mycophenolic Acid / Q000494:pharmacology*; D011685:Purine Nucleotides / Q000378:metabolism; D012254:Ribavirin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D012263:Ribonucleosides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D006454:Hemoglobins; D011685:Purine Nucleotides; D012263:Ribonucleosides; D012254:Ribavirin; D007168:IMP Dehydrogenase; D007658:Ketone Oxidoreductases; D009173:Mycophenolic Acid; C033706:tiazofurin