Induction of Differentiation of HL-60 Human Promyelocytic Leukemic Cells by 3-Deaza Purines

摘要

Two purine analogues, 3-deaza-( + or - ) aristeromycin (3-deazaAri) and 3-deazaguanosine, are capable of inducing terminal differentiation of HL-60 human promyelocytic leukemia cells. However, the biochemical mechanisms of each of the analogues are different. 3-DeazaAri is a potent inhibitor of S-adenosylhomocysteine hydrolase (ADoHcyase) and thus a proximate inhibitor of S-adenosylmethionine (AdoMet) dependent methylation reactions. In contrast, 3-deazaguanosine has no effect on AdoHcyase, but is a potent inhibitor of (IMP) dehydrogenase. Treatment with 3-deazaAri for seven days resulted in inhibition of the proliferation of HL-60 cells. Analysis of the cellular concentrations of AdoMet and AdoHcy by isotopic equilibrium labeling with 35Smethionine revealed a twofold increase in AdoMet, and a 30-fold increase in AdoHcy were treated with 50 micrometer 3-deaza Ari. The increase in AdoMet as presumably due to the inhibition of methylation reactions caused by the large increase in cellular AdoHcy. The results obtained with 3-deazaAri suggest that methylation reactions may regulate the differentiation of HL-60 cells, as in the conversion of 3T3-L1 fibroblasts to adipocytes. It is likely that 3-deazaAri caused an undermethylation of the DNA of HL--60 cells. In support of this is the observation that 5-azacytidine, an inhibitor of DNA methylation, also induces differentiation of HL-60 cells.