Hydroxamide derivatives of short-chain fatty acid have erythropoietic activity and induce γ gene expression in vivo

Abstract

The hydroxamic acid derivatives of short-chain fatty acids, butyryl and propionyl hydroxamate, subericbishydoxamic acid, and suberoylanilide hydroxamic acid, are potent inhibitors of histone deacetylase (HDAC) and have been shown to induce fetal hemoglobin in vitro. In this study we examined whether these compounds have erythropoietic activity and can induce gamma globin gene expression in vivo. Transgenic mice heterozygous for a deletion beta thalassemia and hemizygous for a human gamma globin transgene were treated with these compounds and hematologic responses as well as the induction of gamma gene expression were evaluated. Hematologic studies included measurement of reticulocytes, hematocrit, and the in vivo levels of BFU-E. Effects on globin gene expression were assessed by measuring F reticulocytes and the human gamma/murine alpha globin mRNA ratios by RNAse protection assay. Propionyl and butyryl hydroxamate increased reticulocytes by 71% and 139%, the in vivo BFU-E counts by 75% and 51%, and the in vivo gamma gene expression by 33.9% and 71% respectively. SBHA and SAHA had no erythropoietic activity in vivo. Hydroxamic acid derivatives can stimulate the in vivo erythropoiesis and fetal globin production in a thalassemic murine model. The combined effect of certain histone deacetylase inhibitors on erythropoiesis and on gamma gene expression make these compounds desirable targets for development of therapeutics for beta chain hemoglobinopathies.