Trienone Analogs Of Curcuminoids Induce Fetal Hemoglobin Synthesis Via Demethylation At (G)Gamma-Globin Gene Promoter

The reactivation of gamma-globin chain synthesis to combine with excess free alpha-globin chains and form fetal hemoglobin (HbF) is an important alternative treatment for beta-thalassemia. We had reported HbF induction property of natural curcuminoids, curcumin (Cur), demethoxycurcumin (DMC) and bis-demethoxycurcumin (BDMC), in erythroid progenitors. Herein, the HbF induction property of trienone analogs of the three curcuminoids in erythroleukemic K562 cell lines and primary human erythroid progenitor cells from beta-thalassemia/HbE patients was examined. All three trienone analogs could induce HbF synthesis. The most potent HbF inducer in K562 cells was trienone analog of BDMC (T-BDMC) with 2.4 +/- 0.2 fold increase. In addition, DNA methylation at CpG -53, -50 and +6 of (G)gamma-globin gene promoter in K562 cells treated with the compounds including T-BDMC (9.3 +/- 1.7%, 7.3 +/- 1.7% and 5.3 +/- 0.5%, respectively) was significantly lower than those obtained from the control cells (30.7 +/- 3.8%, 25.0 +/- 2.9% and 7.7 +/- 0.9%, respectively P<0.05). The trienone compounds also significantly induced HbF synthesis in beta-thalassemia/HbE erythroid progenitor cells with significantly reduction in DNA methylation at CpG +6 of (G)gamma-globin gene promoter. These results suggested that the curcuminoids and their three trienone analogs induced HbF synthesis by decreased DNA methylation at (G)gamma-globin promoter region, without effect on (A)gamma-globin promoter region.