5--deoxyadenosine and 9-(tetrahydro-2-furyl)-adenine

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.

Topics: Adenine; Adenosine; Adult; Cell Cycle; Cell Differentiation; Cell Proliferation; Colforsin; Cyclic AMP; Deoxyadenosines; Dideoxyadenosine; Erythroblasts; Erythropoietin; Fetal Hemoglobin; Gene Expression Regulation; Gene Silencing; Globins; Humans; Kinetics; RNA, Messenger; Signal Transduction; Stem Cell Factor; Transforming Growth Factor beta