Pharmacologic treatment of thalassemia intermedia with hydroxyurea

Hajjar, Fouad; Pearson, Howard A.

doi:10.1016/s0022-3476(05)83304-9

Cited by 68 publications

(55 citation statements)

References 7 publications

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“…The anti-proliferative effects of chemotherapeutic agents or the butyrates may thus explain some of the inconsistency in hematological responses observed. The paradoxical finding of initial responses in fetal globin, which are not always followed by increases in total hemoglobin levels, and which then decline over time (perhaps when the growth arrest predominates), has been observed in some thalassemia patients treated with hydroxyurea or butyrates [3,6,32,33].…”

Section: Discussionmentioning

confidence: 99%

Enhancement of growth and survival and alterations in Bcl-family proteins in β-thalassemic erythroid progenitors by novel short-chain fatty acid derivatives

Castañeda

Boosalis

Emery

et al. 2005

Blood Cells, Molecules, and Diseases

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Accelerated apoptosis of erythroid progenitors is a characteristic of β-thalassemia which presents a significant barrier to definitive therapeutic approaches utilizing induction of endogenous fetal globin gene expression. γ-globin gene expression may not be inducible in, or may not be able to rescue, erythroid cells in which programmed cell death is initiated early in erythroblast development. In this report, short-chain fatty acid derivatives (SCFADs) which induce fetal globin gene expression were tested for their ability to promote proliferation and survival of erythroid progenitors cultured from β-thalassemic subjects, and of cytokine-dependent erythroid cell lines. Certain SCFADs promoted thalassemic Bfu-e growth and cytokine-independent growth and survival of erythroid cell lines. A 40-80% increase in erythroid Bfu-e colony number was observed in cultures established with any of five mitogenic SCFADs, compared to control or butyrate-treated cultures from the same subjects. Immunoblot analysis demonstrated that these same SCFADs also regulated the expression of specific protein inhibitors of apoptosis. Antiapoptotic ratios of the proteins Bcl-x L /Bcl-x S in thalassemic Bfu-e were increased by 30-120% with exposure to the SCFDs, compared to the ratios in the same cells cultured under control conditions. Similar anti-apoptotic increases in Mcl-1 L /Mcl-1 S ratios were induced by the SCFADs. These findings suggest that select fetal globin-inducing SCFADs which enhance proliferation of β-thalassemia progenitors may enhance survival of these progenitors by altering levels of Bcl-family protein members. This combination of effects should enhance erythroid cell survival in the β-thalassemia syndromes, allowing fetal globin gene expression to be induced more effectively than currently available, growth-suppressing, fetal globin-inducing agents, such as the butyrates or chemotherapeutic agents.

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Section: Discussionmentioning

confidence: 99%

Enhancement of growth and survival and alterations in Bcl-family proteins in β-thalassemic erythroid progenitors by novel short-chain fatty acid derivatives

Castañeda

Boosalis

Emery

et al. 2005

Blood Cells, Molecules, and Diseases

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“…36 In patients with thrombocytosis and a large number of circulating erythroblasts after splenectomy, the administration of hydroxyurea might be helpful. Hydroxyurea has been used in TI to enhance hemoglobin F synthesis, 43 whereas an additional benefit in patients with PHT would be the restriction of thrombocytosis and the reduction of circulating myeloid elements. The use of antiplatelet agents has also been proposed for patients who have thalassemia with thrombocytosis and hypoxemia, but it could be dangerous for patients with PXE-like lesions, which predispose to hemorrhagic disorders.…”

Section: Therapeutic Considerationsmentioning

confidence: 99%

Cardiac involvement in thalassemia intermedia: a multicenter study

Aessopos

Farmakis

Karagiorga

et al. 2001

Blood

254

261

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Cardiac complications in 110 patients (mean age, 32.5 ؎ 11.4 years) with thalassemia intermedia (TI) were studied. Sixtyseven (60.9%) of them had not been transfused or were minimally transfused (group A). The rest had started transfusions after the age of 5 years (mean, 15.1 ؎ 10.1 years), initially on demand and later more frequently (group B). Overall mean hemoglobin and ferritin levels were 9.1 ؎ 1.1 g/dL and 1657 ؎ 1477 ng/mL, respectively. Seventy-six healthy controls were also studied. The investigation included thorough history taking, clinical examination, electrocardiography, chest radiograph, and full resting echocardiography. Of 110 patients, 6 (5.4%) had congestive heart failure (CHF), and 9 (8.1%) had a history of acute pericarditis. Echocardiography showed pericardial thickening, with or without effusion, in 34.5% of the patients.

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“…3,4 However, toxicity associated with these agents and other issues has prevented their widespread use. Although hydroxyurea has been approved by the Food and Drug Administration (FDA) as an HbF-inducing agent, its use has been limited because it is effective in only approximately half of SCD patients, 5 it is less effective in ␤-thal, 6 and it has a low therapeutic index because of suppression of blood counts, making close monitoring a necessity. Because of these and other concerns, hydroxyurea is significantly under used in both the United States 7 and Africa.…”

Section: Introductionmentioning

confidence: 99%

Simvastatin and t-butylhydroquinone suppress KLF1 and BCL11A gene expression and additively increase fetal hemoglobin in primary human erythroid cells

Macari

Schaeffer

West

et al. 2013

Blood

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Key Points• Simvastatin and tBHQ suppress KLF1 and BCL11 gene expression and additively increase fetal hemoglobin in primary human erythroid cells.• Because both drugs are FDAapproved, these findings could lead to clinical trials in the relatively near future.Although increased fetal hemoglobin (HbF) levels have proven benefit for people with ␤-hemoglobinopathies, all current HbF-inducing agents have limitations. We previously reported that drugs that activate the NRF2 antioxidant response signaling pathway increase HbF in primary human erythroid cells. In an attempt to increase HbF levels achieved with NRF2 activators, in the present study, we investigated potential complementary activity between these agents and HMG-CoA reductase inhibitors (statins) based on their ability to induce KLF2 protein levels. Experiments in K562 cells showed that simvastatin increased KLF2 mRNA and protein and KLF2 binding to HS2 of the ␤-globin locus control region and enhanced ␥-globin mRNA production by the NRF2 activator Tert-butylhydroquinone (tBHQ). When tested in differentiating primary human erythroid cells, simvastatin induced HbF alone and additively with tBHQ, but it did not increase KLF2 mRNA or locus control region binding above levels seen with normal differentiation. Investigating alternative mechanisms of action, we found that both simvastatin and tBHQ suppress ␤-globin mRNA and KLF1 and BCL11A mRNA and protein, similar to what is seen in people with an HPFH phenotype because of KLF1 haploinsufficiency. These findings identify statins as a potential class of HbF-inducing agents and suggest a novel mechanism of action based on pharmacologic suppression of KLF1 and BCL11A gene expression. IntroductionThe ␤-hemoglobinopathies are inherited disorders caused by mutations that alter ␤-globin protein structure (eg, sickle cell disease, SCD) or gene expression (eg, ␤-thalassemia, ␤-thal). In contrast to most genetic diseases, humans have 2 potential replacement genes, the ␥-globin genes, which are expressed during fetal development but then silenced soon after birth. When these genes are expressed in adults with ␤-hemoglobinopathies as a result of mutations, the clinical manifestations of SCD and ␤-thal are greatly improved because of the ability of the ␥-globin protein to inhibit sickle Hb polymerization and to reduce the globin chain imbalance of ␤-thal. 1,2 This has led to a 3-decade-long search for pharmacologic agents that can reactivate ␥-globin gene expression and fetal hemoglobin (HbF) production. Proof-of-principle studies using DNA methyltransferase inhibitors in small numbers of near endstage ␤-thal and SCD patients have shown that significant clinical benefits can be achieved. 3,4 However, toxicity associated with these agents and other issues has prevented their widespread use. Although hydroxyurea has been approved by the Food and Drug Administration (FDA) as an HbF-inducing agent, its use has been limited because it is effective in only approximately half of SCD patients, 5 it is less effective in ␤-thal, 6 a...

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Pharmacologic treatment of thalassemia intermedia with hydroxyurea

Cited by 68 publications

References 7 publications

Enhancement of growth and survival and alterations in Bcl-family proteins in β-thalassemic erythroid progenitors by novel short-chain fatty acid derivatives

Enhancement of growth and survival and alterations in Bcl-family proteins in β-thalassemic erythroid progenitors by novel short-chain fatty acid derivatives

Cardiac involvement in thalassemia intermedia: a multicenter study

Simvastatin and t-butylhydroquinone suppress KLF1 and BCL11A gene expression and additively increase fetal hemoglobin in primary human erythroid cells

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