ABSTRACT
Other than hydroxyurea, no pharmacologic agents are clinically available for fetal hemoglobin (HbF) induction in sickle cell disease (SCD). An optimal candidate would induce HbF without causing cell cycle inhibition and would act independently of hydroxyurea in order to yield additional HbF induction when combined. We explored whether inhibition of histone deacetylase (HDAC) 1 or HDAC2 could achieve these goals. In human erythroid progenitor cells, shRNA knockdown of the HDAC1 or HDAC2 genes induced gamma globin, without altering cellular proliferation in vitro, and without altering cell cycle phase. Treatment with hydroxyurea in combination with HDAC2 knockdown yielded a further increase in gamma globin expression. Additionally, when CD34+ cells were treated with both hydroxyurea and MS-275 (an inhibitor of HDAC 1, 2, and 3), an additive induction of relative gamma globin expression was achieved. Our findings support further clinical investigation of HDAC inhibitors in combination with hydroxyurea in SCD patients.
Subject(s)
Bone Marrow Cells/metabolism , Cell Cycle/genetics , Histone Deacetylase 1/antagonists & inhibitors , Histone Deacetylase 2/antagonists & inhibitors , gamma-Globins/agonists , Bone Marrow Cells/cytology , Bone Marrow Cells/drug effects , Cell Cycle/drug effects , Cell Differentiation , Gene Expression/drug effects , Gene Knockdown Techniques , Genetic Vectors , Histone Deacetylase 1/genetics , Histone Deacetylase 1/metabolism , Histone Deacetylase 2/genetics , Histone Deacetylase 2/metabolism , Humans , Hydroxyurea/pharmacology , Lentivirus/genetics , Primary Cell Culture , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , beta-Globins/genetics , beta-Globins/metabolism , gamma-Globins/genetics , gamma-Globins/metabolismABSTRACT
Thalassemia is an inherited disorder of hemoglobin molecules that is characterized by an imbalance of α- and ß-globin chain synthesis. Accumulation of unbound α-globin chains in erythroid cells is the major cause of pathology in ß-thalassemia. Stimulation of γ-globin production can ameliorate disease severity as it combines with the α-globin to form fetal hemoglobin. We examined γ-globin-inducing effect of curcuminoids extracted from Curcuma longa L. and their metabolite reduced forms in erythroid leukemia K562 and human primary erythroid precursor cells. The results showed that curcuminoid compounds, especially bisdemethoxycurcumin are potential γ-globin enhancers. We also demonstrated that its reduced analog, hexahydrobisdemethoxycurcumin (HHBDMC), is most effective and leads to induction of γ-globin mRNA and HbF in primary erythroid precursor cells for 3.6 ± 0.4- and 2.0 ± 0.4-folds, respectively. This suggested that HHBDMC is the potential agent to be developed as a new therapeutic drug for ß-thalassemia and related ß-hemoglobinopathies.
