Inhibition of erythroblast growth and fetal hemoglobin production by ribofuranose-substituted adenosine derivatives.
In vivo, inhibition of fetal hemoglobin (HbF) expression in humans around the time of birth causes the clinical manifestation of sickle cell and beta-thalassemia syndromes. Inhibition of HbF among cultured cells was recently described by the adenosine derivative molecule named SQ22536. Here, a primary cell culture model was utilized to further explore the inhibition of HbF by adenosine derivative molecules. SQ22536 demonstrated down-regulation of growth and HbF expression among erythroblasts cultured from fetal and adult human blood. The effects upon HbF were noted in a majority of cells, and quantitative PCR analysis demonstrated a transcriptional mechanism. Screening assays demonstrated that two additional molecules named 5'-deoxy adenosine and 2',3'-dideoxy adenosine had effects on HbF comparable to SQ22536. Other adenosine derivative molecules, adenosine receptor binding ligands, and cAMP-signaling regulators failed to inhibit HbF in matched cultures. These results suggest that structurally related ribofuranose-substituted adenosine analogues act through an unknown mechanism to inhibit HbF expression in fetal and adult human erythroblasts.
Bhanu
Natarajan V
NV
Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Laboratory Medicine Department, Hematology Service, National Institutes of Health, Bethesda, MD 20892, USA.
Lee
Y Terry
YT
Oneal
Patricia A
PA
Gantt
Nicole M
NM
Aerbajinai
Wulin
W
Noel
Pierre
P
Thomas
Craig J
CJ
Miller
Jeffery L
JL
D000225:Adenine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000241:Adenosine / Q000737:chemistry / Q000494:pharmacology*; D000328:Adult; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003839:Deoxyadenosines / Q000737:chemistry / Q000494:pharmacology; D016048:Dideoxyadenosine / Q000737:chemistry / Q000494:pharmacology; D004900:Erythroblasts / Q000166:cytology* / Q000187:drug effects*; D004921:Erythropoietin / Q000494:pharmacology; D005319:Fetal Hemoglobin / Q000096:biosynthesis*; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D005914:Globins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019089:Stem Cell Factor / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D003839:Deoxyadenosines; D012333:RNA, Messenger; D019089:Stem Cell Factor; D016212:Transforming Growth Factor beta; D004921:Erythropoietin; C017759:9-(tetrahydro-2-furyl)-adenine; D005576:Colforsin; C033714:5'-deoxyadenosine; D016048:Dideoxyadenosine; D005914:Globins; D005319:Fetal Hemoglobin; D000242:Cyclic AMP; D000225:Adenine; D000241:Adenosine