Effects of hydroxyurea on F‐cells in sickle cell disease and potential impact of a second fetal globin inducer

Dai, Yan; Sangerman, Jose; Nouraie, Mehdi; Faller, Aidan D; O'Neal, Patricia; Rock, Angela; Owoyemi, Oluwakemi; Niu, Xiaomei; Nekhai, Sergeï; Maharaj, Dashmeet; Cui, Shauiying; Taylor, Robert E.; Steinberg, Martin H.; Perrine, Susan P.

doi:10.1002/ajh.24590

Cited by 8 publications

(6 citation statements)

References 6 publications

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“…HU has more effect in increasing F-cells. A combination of HU with a second HbF inducer increased more HbF expression in sickle cell disease patients as the second HbF inducer produce higher concentrations of HbF content in erythroid cells primed by HU, which in turn contribute to higher total HbF 23 . Although a higher % F-cells and HbF expression per cells is anticipate in a longer treatment than 4 days reported here.…”

Section: Discussionmentioning

confidence: 97%

Trienone analogs of curcuminoids induce fetal hemoglobin synthesis via demethylation at Gγ-globin gene promoter

Nuamsee

Chuprajob

Pabuprapap

et al. 2021

Sci Rep

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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.

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Section: Discussionmentioning

confidence: 97%

Trienone analogs of curcuminoids induce fetal hemoglobin synthesis via demethylation at Gγ-globin gene promoter

Nuamsee

Chuprajob

Pabuprapap

et al. 2021

Sci Rep

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“…It has been used for a different activity in combination with Ldopa to enhance its half-life for the treatment of Parkinson's disease for > 40 years in Europe and Canada. 123,124 It was discovered in a high throughput screen of clinical-stage drugs to have high inducing activity compared to other active and non-cyotoxic candidates. 104,105 Benserazide profoundly suppressed or displaced several repressors of the fetal globin gene promoter in patients' erythroid progenitors and induced γ globin mRNA and protein, F-reticulocytes, F-cells, and total Hb in nonhuman primates and transgenic mice.…”

Section: Targeted Inhibitors Of Multiple Repressorsmentioning

confidence: 99%

Pharmacologic Therapies in Beta Hemoglobinopathies: Fetal Globin Gene Induction in the First Molecular Diseases

Kuo,

Faller,

Lavelle

et al. 2024

MRAJ

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Beta hemoglobinopathies and thalassemias are caused by diverse molecular mutations of the βA globin chains and modulated by polymorphisms. These are important disorders in medical history, as they became prevalent globally in regions where P. falciparum malaria was endemic. Heterozygous or carrier states conferred a survival advantage; however, doubly heterozygous or homozygous states cause severe hemolytic anemia and multi-organ complications. These disorders are somewhat unique in that all humans have alternate genes for fetal globin chains, which are expressed in fetal life but are silenced on a developmental clock in infancy. An established approach to ameliorating conditions of abnormal adult globin genes is to reactivate, or increase expression, of the endogenous fetal globin genes to replace the missing protein chains in beta thalassemias or inhibit polymerization of hemoglobin S and reduce the red cell abnormalities. This review provides a high-level overview of cell and molecular mechanisms that mediate fetal to adult globin gene switching and pharmacologic therapies that can reactivate fetal globin through different actions. Intermittent or metronomic dosing regimens have overcome challenges of undesirable off-target effects by agents that cause erythroid cell growth arrest. Multiple pharmacologic candidates reactivate or increase the expression of fetal globin protein and proportions of red blood cells containing HbF (F-cells). Hydroxyurea maintains high levels of HbF if begun in infancy, with some decline in mid-childhood. It elicits lower responses in HbF in adult patients, but still has broad clinical benefit in reducing many complications. However, many adult patients do not tolerate optimal hydroxyurea dosing due to cytopenias. Parenterally administered therapies with differing molecular actions, such as demethylating agents and histone deacetylase inhibitors, have shown proof-of-principle in reactivating HbF. Orally bioavailable candidates with complementary molecular mechanisms are in trials. Combining fetal globin-inducing agents with other therapies with complementary mechanisms, such as recombinant erythropoietin that promotes the survival of red blood cells and therapeutics that promote erythroid cell metabolism, should have additive effects. These pharmaceutical candidates offer great clinical potential and global feasibility for ameliorating these serious diseases.

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“…Benserazide is a peripheral dopa decarboxylase inhibitor used in combination with L-DOPA for treatment of Parkinson's disease. In preclinical models, benserazide was shown to induce HbF production [133,134]. Benserazide was also shown to increase fetal γ-globin gene transcription and the proportions of cells expressing HbF (F reticulocytes and F cells) in erythroid precursors from patients with HbE-β 0 -thalassemia and SCD [133,135].…”

Section: Benserazidementioning

confidence: 99%

“…In preclinical models, benserazide was shown to induce HbF production [133,134]. Benserazide was also shown to increase fetal γ-globin gene transcription and the proportions of cells expressing HbF (F reticulocytes and F cells) in erythroid precursors from patients with HbE-β 0 -thalassemia and SCD [133,135]. An observational study by Santos et al on a total of 50 individuals was conducted to evaluate the ability of benzeraside (at daily doses that ranged from 100 mg to 700 mg) to increase HbF production and circulating F cells.…”

Section: Benserazidementioning

confidence: 99%

Pharmacological Induction of Fetal Hemoglobin in β-Thalassemia and Sickle Cell Disease: An Updated Perspective

et al. 2022

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A significant amount of attention has recently been devoted to the mechanisms involved in hemoglobin (Hb) switching, as it has previously been established that the induction of fetal hemoglobin (HbF) production in significant amounts can reduce the severity of the clinical course in diseases such as β-thalassemia and sickle cell disease (SCD). While the induction of HbF using lentiviral and genome-editing strategies has been made possible, they present limitations. Meanwhile, progress in the use of pharmacologic agents for HbF induction and the identification of novel HbF-inducing strategies has been made possible as a result of a better understanding of γ-globin regulation. In this review, we will provide an update on all current pharmacological inducer agents of HbF in β-thalassemia and SCD in addition to the ongoing research into other novel, and potentially therapeutic, HbF-inducing agents.

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Effects of hydroxyurea on F‐cells in sickle cell disease and potential impact of a second fetal globin inducer

Cited by 8 publications

References 6 publications

Trienone analogs of curcuminoids induce fetal hemoglobin synthesis via demethylation at Gγ-globin gene promoter

Trienone analogs of curcuminoids induce fetal hemoglobin synthesis via demethylation at Gγ-globin gene promoter

Pharmacologic Therapies in Beta Hemoglobinopathies: Fetal Globin Gene Induction in the First Molecular Diseases

Pharmacological Induction of Fetal Hemoglobin in β-Thalassemia and Sickle Cell Disease: An Updated Perspective

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