Trienone analogs of curcuminoids induce fetal hemoglobin synthesis via demethylation at G\u03b3-globin gene promoter

Khanita Nuamsee,Pornthip Chaichompoo,Jim Vadolas,Saovaros Svasti,Wachirachai Pabuprapap,Pornrutsami Jintaridth,Thongperm Munkongdee,Phatchariya Phannasil,Apichart Suksamrarn,Thipphawan Chuprajob

doi:10.1038/s41598-021-87738-2

Abstract

The reactivation of γ-globin chain synthesis to combine with excess free α-globin chains and form fetal hemoglobin (HbF) is an important alternative treatment for β-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 β-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 Gγ-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 β-thalassemia/HbE erythroid progenitor cells with significantly reduction in DNA methylation at CpG + 6 of Gγ-globin gene promoter. These results suggested that the curcuminoids and their three trienone analogs induced HbF synthesis by decreased DNA methylation at Gγ-globin promoter region, without effect on Aγ-globin promoter region.

Highlights

The reactivation of γ-globin chain synthesis to combine with excess free α-globin chains and form fetal hemoglobin (HbF) is an important alternative treatment for β-thalassemia
The HbF inducing property of trienone analogs of curcuminoids was first examined in K562:ΔGγ-Aγ EGFP reporter cells, a promoterEGFP reporter, harboring enhance green fluorescent protein (EGFP) under control of the Gγ-globin promoter[16]
Cell viability of the cells treated with BDMC, 92.1 ± 2.9%, and trienone analog of BDMC (T-BDMC), 91.6 ± 2.6%, was higher than cells treated with 20 μM cisplatin, 76.8 ± 1.8% (Fig. 2b)

Summary

Introduction

The reactivation of γ-globin chain synthesis to combine with excess free α-globin chains and form fetal hemoglobin (HbF) is an important alternative treatment for β-thalassemia. The trienone compounds significantly induced HbF synthesis in β-thalassemia/HbE erythroid progenitor cells with significantly reduction in DNA methylation at CpG + 6 of Gγ-globin gene promoter. These results suggested that the curcuminoids and their three trienone analogs induced HbF synthesis by decreased DNA methylation at Gγ-globin promoter region, without effect on Aγ-globin promoter region. Effects of the curcuminoids and their trienone analogs on HbF synthesis and DNA methylation at both Gγ- and Aγ-globin gene promoters in K562 cells and primary human erythroid progenitors from β-thalassemia/HbE patients were examined. We found that HbF synthesis was induced by the trienone compounds and decreased DNA methylation level at Gγ-globin gene promoter was observed

Methods

Results

Conclusion