Inhibition of erythroblast growth and fetal hemoglobin production by ribofuranose-substituted adenosine derivatives

Natarajan V. Bhanu, Y. Terry Lee, Patricia A. Oneal, Nicole M. Gantt, Wulin Aerbajinai, Pierre Noel, Craig J. Thomas, Jeffery L. Miller

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)504-510
Number of pages7
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1782
Issue number9
DOIs
StatePublished - Sep 2008

Keywords

  • Adenosine derivative
  • Cytokine
  • HbF inhibition
  • Hemoglobinopathy
  • Human erythropoiesis
  • SQ22536

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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