Induction of fetal hemoglobin expression by the histone deacetylase inhibitor apicidin

Abstract

Pharmacologic stimulation of fetal hemoglobin (HbF) expression may be a promising approach for the treatment of ␤-thalassemia. In this study, we have investigated the HbF-inducing activity and molecular mechanisms of specific histone deacetylase (

Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease

“…HDAC inhibition has previously been established as a route to fetal hemoglobin induction. Indeed, the observed induction of γ-globin in human subjects treated with sodium butyrate and sodium valproate has been linked to weak HDAC inhibitory activity (22)(23)(24)(25). Despite extensive research in this area, the specific targets among the 18 known human enzymes are not known, in part because of the perceived nonselective action of investigational and tool compounds.…”

Fetal hemoglobin chemical inducers for treatment of hemoglobinopathies

“…Several HDAC inhibitors, such as sodium butyrate, adipicin, scriptaid and trichostatin A (TSA), have been shown to induce HbF synthesis in vitro; butyrate induced HbF synthesis in humans, and it will be analyzed below in a separate chapter. Particularly, in vitro studies carried out both in erythroleukemia cell lines and in primary erythroid cultures have shown that TSA [107,108], MS-275, and scriptaid [106,109] and apicidin [110] simulate HbF synthesis.…”

“…Clinical studies reported increased HbF levels in patients treated with valproic acid for epilepsy [115,116], and subsequently, this compound was used in small series of patients with sickle cell anemia [117][118][119]. However, the stimulatory effect of valproic acid on HbF synthesis was only weak, reflecting the relatively modest HbF inducing potency of valproic acid in erythroid cells in vitro [120,121]. Recently, valproic acid derivatives have been synthesized exhibiting a higher HbF-inducing activity in vitro, but the activity of these compounds in vivo remains to be evaluated [122].…”

Understanding mechanisms of γ‐globin gene regulation to develop strategies for pharmacological fetal hemoglobin induction

“…Histone deacetylase (HDAC) enzymes produce deacetylation of histone tails, causing chromatin condensation and transcriptional silencing. Several HDAC inhibitors, such as sodium butyrate, trichostatin A, adicipin, and scriptaid, have been shown to induce Hb F synthesis in vitro; butyrate also induced Hb F in humans (Perrine et al, 1988;Atweh et al, 1999;Cao et al, 2004;Witt et al, 2003;Johnson et al, 2005). Although these agents have in common the ability to induce histone hyperacetylation, more recently various cell signaling pathways have been implicated to produce augmented transfactor interaction in the ␥-globin promoter to enhance the transcriptional machinery.…”