Document Detail

Enhancement of hemoglobin and F-cell production by targeting growth inhibition and differentiation of K562 cells with ribonucleotide reductase inhibitors (didox and trimidox) in combination with streptozotocin.
MedLine Citation:
PMID:  10706760     Owner:  NLM     Status:  MEDLINE    
Upon appropriate drug treatment, the human erythroleukemic K562 cells have been shown to produce hemoglobin and F-cells. Fetal hemoglobin (Hb F) inhibits the polymerization events of sickle hemoglobin (Hb S), thereby ameliorating the clinical symptoms of sickle cell disease. Ribonucleotide reductase inhibitors (RRIs) have been shown to inhibit the growth of myeloid leukemia cells leading to the production of Hb F upon differentiation. Of the RRIs currently in use, hydroxyurea is the most effective agent for Hb F induction. We have examined the capacity of two novel RRIs, didox (DI) and trimidox (TRI), in combination with streptozotocin (STZ), to induce hemoglobin and F-cell production. The K562 cells were cultured with different concentrations of didox-STZ or trimidox-STZ at a fixed molar ratio of 3:1 and 1:5 for 96 hr, respectively. At pre-determined time intervals, aliquots of cells were obtained and total hemoglobin (benzidine positive) levels, number of F-cells, and Hb F were determined by the differential staining technique, fetal hemoglobin assay kit, and fluorescence cytometry respectively. The effect of combined drug treatment on the growth of K562 cells was examined by isobologram analysis. Our results indicate that a synergistic growth-inhibitory differentiation effect occurred when didox or trimidox was used in combination with STZ on K562 cells. There was an increase in the number of both benzidine-positive normoblasts and F-cells, accompanied by morphologic appearances typical of erythroid maturation. On day 4, the number of benzidine-positive cells showed a 6-9-fold increase and the number of F-cells was between 2.5- and 5.7-fold higher than the respective controls. Based upon these results, treatment with a ribonucleotide reductase inhibitor, such as didox or trimidox, in combination with STZ, might offer an additional promising option in sickle cell disease therapy.
W E Iyamu; S E Adunyah; H Fasold; K Horiuchi; H L Elford; T Asakura; E A Turner
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  American journal of hematology     Volume:  63     ISSN:  0361-8609     ISO Abbreviation:  Am. J. Hematol.     Publication Date:  2000 Apr 
Date Detail:
Created Date:  2000-04-18     Completed Date:  2000-04-18     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  7610369     Medline TA:  Am J Hematol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  176-83     Citation Subset:  IM    
Copyright Information:
Copyright 2000 Wiley-Liss, Inc.
Comprehensive Sickle Cell Center, Meharry Medical College, Nashville, Tennessee, USA.
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MeSH Terms
Antineoplastic Agents / therapeutic use
Benzamidines / pharmacology*,  therapeutic use
Cell Differentiation / drug effects
Cell Division / drug effects
Drug Therapy, Combination
Enzyme Inhibitors / pharmacology*
Fetal Hemoglobin / biosynthesis*
Hemoglobin, Sickle / biosynthesis*
Hydroxamic Acids / pharmacology*,  therapeutic use
K562 Cells / cytology*,  metabolism
Ribonucleotide Reductases / antagonists & inhibitors
Streptozocin / therapeutic use*
Grant Support
2P60 H13832//PHS HHS; P60 HL33737/HL/NHLBI NIH HHS; U24 HL 58930/HL/NHLBI NIH HHS
Reg. No./Substance:
0/3,4,5-trihydroxybenzamidoxime; 0/Antineoplastic Agents; 0/Benzamidines; 0/Enzyme Inhibitors; 0/Hemoglobin, Sickle; 0/Hydroxamic Acids; 18883-66-4/Streptozocin; 69839-83-4/3,4-dihydroxybenzohydroxamic acid; 9034-63-3/Fetal Hemoglobin; EC 1.17.4.-/Ribonucleotide Reductases

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