Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: KEGG:D02003 (NBT)
 1,323 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inosine-5'-monophosphate (IMP) dehydrogenase catalyzes the rate-limiting reaction of guanine nucleotide biosynthesis and has been implicated in the reaction of cell growth and differentiation. We examined the ability of mizoribine, an IMP dehydrogenase inhibitor, to induce differentiation in HL-60 and U937 cells as well as in fresh leukemic blast cells from patients with non-lymphocytic leukemia. Treatment with mizoribine reduced intracellular GTP levels and induced morphologic and functional differentiation in these two cell lines in a dose-dependent manner. HL-60 and U937 cells developed polymorphic nuclei and macrophage-like cytoplasm, respectively, as well as expression of CD11b and CD14 antigens and the ability to oxidize NBT. These changes became evident when intracellular GTP levels decreased to approximately 30% of untreated controls and were abrogated by addition of guanosine to the media. However, in fresh leukemic cells, the cells showing maturation in response to mizoribine were limited in those derived from two of ten patients having non-lymphocytic leukemia. These findings suggest mizoribine could induce differentiation in HL-60 and U937 cells through a decrease of intracellular GTP levels. Further study is required to determine its clinical use in patients with acute non-lymphocytic leukemia.
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PMID:Differentiation induction in non-lymphocytic leukemia cells upon treatment with mizoribine. 940 Dec 79

3-Hydrogenkwadaphnin (3-HK) is a new diterpene ester, recently isolated from the leaves of Dendrostellera lessertii with potent anti-tumoral and anti-metastatic activities. Herein, we report that 3-HK induces differentiation and apoptosis in HL-60 cells. The drug at 2.5 - 40 nM inhibited proliferation of HL-60 cells after 24 - 96 h of treatment. Cell viability was also decreased by 57 % after 96 h treatment with the drug. NBT reducing assay and phagocytic activity revealed that the inhibition of proliferation is associated with differentiation especially toward macrophages-like morphology. Indeed, the drug at 2.5 - 10 nM induced differentiation by 5 - 49 % in HL-60 cells. Acridine orange/ethidium bromide (AO/EtBr) double staining and DNA fragmentation assays revealed that apoptosis occurred after differentiation of HL-60 cells. Guanosine at 50 microM decreased the apoptotic cell death and the differentiation caused by the drug. Therefore, GTP depletion, as a result of inhibition of inosine monophosphate dehydrogenase (IMPDH), is considered as one of the main reasons for differentiation and apoptotic cell death by this new drug.
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PMID:3-Hydrogenkwadaphnin from Dendrostellera lessertii induces differentiation and apoptosis in HL-60 cells. 1639 46

3-Hydrogenkwadaphnin (3-HK) (Fig. 1) is a daphnane-type diterpene ester isolated from the leaves of Dendrostellera lessertii (Thymelaeaceae) with differentiation and apoptotic potency among several leukemic cells without any measurable adverse effects on normal cells [Moosavi, M.A., Yazdanparast, R., Sanati, M.H., Nejad, A.S., 2005a. 3-Hydrogenkwadaphnin targets inosine 5'-monophosphate dehydrogenase and triggers post-G1 arrest apoptosis in human leukemia cell lines. Int. J. Biochem. Cell Biol. 37, 2366-2379]. In this study, we evaluated differentiating and apoptotic efficiency of a second new anti-proliferating agent from the same plant relative to 3-HK using acute myeloid leukemia (AML) KG1 cell line. 3-HK at 5-30 nM inhibited proliferation of KG1 cells after 24-96 h of treatment. NBT reducing assay and expression of cell surface markers (CD11b and CD14) confirmed that the inhibition of proliferation is associated with differentiation toward macrophage-like morphology. Regarding the relatively weaker potency of 3-HK in the induction of differentiation compared to that of the crude extract, we looked for additional compound(s) with similar properties in the crude extract. This effort led to isolation of the second compound from the leaves' extract with higher differentiating potency. The new compound inhibited proliferation of KG1 cells by almost 48+/-3.1% after 72 h of treatment with a single dose of 1.5 microg/ml. The treated cells differentiated along the monocyte/macrophage lineage based on the morphological features apparent after Wright-Giemsa staining, phagocytic activity and expression of cell surface markers as analyzed by flow cytometry. On the other hand, the results indicated that exposure of KG1 cells to either 3-HK or the new compound for 3-4 days induced apoptosis as assayed qualitatively by acridine orange/ethidium bromide (Ao/EtBr) double staining, agarose gel electrophoresis and quantitatively by Annexin-V technique and sub-G1 DNA staining using flow cytometry. Based on the present data, these two active constituents of D. lessertii have the novelty of being further evaluated for pharmaceutical applications.
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PMID:3-Hydrogenkwadaphnine, a novel diterpene ester from Dendrostellera lessertii, its role in differentiation and apoptosis of KG1 cells. 1882 78