Cellular and molecular effects of a pulse butyrate regimen and new inducers of globin gene expression and hematopoiesis

Tohru Ikuta, George Atweh, Vassiliki Boosalis, Gary L. White, Silvana D.A. Fonseca, Michael Boosalis, Douglas V. Faller, Susan P. Perrine

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Cooley's anemia is characterized by a deficiency of β-globin chains, a relative excess of α-globin chains, and consequent accelerated programmed death of developing erythroid cells in the bone marrow. Increasing expression of the γ-globin genes to adequately balance excess α-globin chains can ameliorate this disorder. Butyrates induce γ-globin experimentally, but can also cause cell growth arrest with prolonged exposure or high concentrations, which in turn can accelerate apoptosis. To determine if these potentially opposing effects can be balanced to enhance therapeutic efficacy, an intermittent 'pulsed' regimen of butyrate was evaluated. Following induction of γ-globin mRNA and protein synthesis, total hemoglobin increased in β-thalassemia patients by more than 2 g/dl above baseline, and Hb F increased above 20% in 5/8 sickle cell patients from baseline levels of 2% Hb F. Specific regulatory regions were identified in the γ- and β-globin gene promoters to which new binding of transcription factors, including αCP2 (an activator of γ globin) occur during therapy solely in the butyrate-responsive patients. Other compounds which induce γ globin, derivatives of acetic, phenoxyacetic, propionic, and cinnamic acids, and dimethylbutyrate, are under investigation. Some of these newer γ-globin inducers (designated hemokines) provide better potential as therapeutics by also acting to increase hematopoietic cell viability and proliferation. Pharmacologic induction of expression of the endogenous γ-globin genes is a realistic approach to therapy of the β-globin disorders for many patients, with some effective agents available now and new therapeutics, with enhanced activities, under development.

Original languageEnglish (US)
Pages (from-to)87-99
Number of pages13
JournalAnnals of the New York Academy of Sciences
Volume850
DOIs
StatePublished - Jan 1 1998
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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