Future
Editorial Special Focus Issue: Rare Diseases
For reprint orders, please contact [email protected]
Medicinal Chemistry
What are the most promising emerging therapies for sickle cell disease? “Regadenoson is a selective A
adenosine agonist and its use to treat sickle cell 2 anemia is under investigation in clinical studies.
”
Keywords: fetal hemoglobin inducers • inflammation • new drugs • nitric oxide • sickle cell disease • vaso-occlusion
Sickle cell disease (SCD) is a chronic hereditary hemolytic anemia characterized by a single nucleotide mutation (GTG to GAG) in the sixth codon of the gene encoding β-globin, causing the replacement of glutamic acid with a valine residue in the protein forming the β-globin chain. Chronic inflammation, vasculopathy, microvascular vaso-occlusion and acute/chronic multi organ damage contribute to the main clinical symptoms of SCD [1] . The disease originated approximately 50,000–100,000 years ago in the countries of central and western Africa, India and east Asia. However, it has since spread worldwide as a result of slave trafficking in past centuries and racial intermixing. SCD is one of the most common hereditary hemoglobinopathies, affecting more than 60,000 homozygous African–American individuals and approximately 250,000 newborns annually throughout the world [2] . In environments of low oxygen tension, the substitution of glutamic acid (βGlu6) with valine (βVal6) in the β-chain of hemoglobin exposes the hydrophobic residues that induce the polymerization of hemoglobin S (HbS) molecules. The mutant polymers alter the cytoskeletal structure of red blood cells (RBCs), generating sickle-like cells. The polymeric fibers also damage the RBC membrane, causing hemolysis and reducing the numbers of RBCs, causing anemia in the affected individuals. RBC hemolysis is followed by the extravasation of the cellular contents, including hemoglobin and arginase. Arginase reduces the concentra-
10.4155/FMC.14.55 © 2014 Future Science Ltd
tion of arginine, which is used by endothelial NO synthase to produce NO. The heme group present in the released hemoglobin can also sequester endothelial NO, contributing to a ‘vasoconstriction’ phenotype in SCD patients. These low levels of NO also contribute to vaso-occlusion. This process is characterized by a strong interaction between RBCs, white blood cells and platelets, which also interact with the vascular endothelium since the expression of adhesion molecules is increased in vessel. These heterocellular aggregates then obstruct blood flow, leading to hypoxia in the adjacent vasculature. The injury to the vascular endothelium caused by sickle cell aggregates and the involvement of white blood cells in the vasoocclusion process increase the levels of pro inflammatory cytokines and contribute to the chronic inflammation in SCD patients. Vaso-occlusion is responsible for the main clinical events of SCD, which include retinopathy, acute chest syndrome, pulmonary hypertension, priapism, stroke, splenic sequestration, pain and splenic infarction [3,4] . Little progress has been made in the development of pharmacotherapies for SCD since its first description in 1910 by James Herrick, who observed anomalous sickle-shaped RBCs in a patient with severe anemia [5] . The lack of interest by the pharmaceutical industry and the paucity of specific treatments for SCD are among the harshest aspects of this disease. Today, hydroxyurea (HU), a ribonucleotide reductase inhibitor, is the only drug
Future Med. Chem. (2014) 6(9), 979–982
Thais Regina Ferreira de Melo Laboratório de Pesquisa e Desenvolvimento de Fármacos, Departamento de Fármacos e Medicamentos, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista–UNESP, Rodovia Araraquara Jaú Km 01, 14801-902, Araraquara, São Paulo, Brasil
Chung Man Chin Laboratório de Pesquisa e Desenvolvimento de Fármacos, Departamento de Fármacos e Medicamentos, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista–UNESP, Rodovia Araraquara Jaú Km 01, 14801-902, Araraquara, São Paulo, Brasil
Jean Leandro dos Santos Author for correspondence: Laboratório de Pesquisa e Desenvolvimento de Fármacos, Departamento de Fármacos e Medicamentos, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista–UNESP, Rodovia Araraquara Jaú Km 01, 14801-902, Araraquara, São Paulo, Brasil Tel.: +55 16 33016972 Fax: +55 16 33016960 [email protected]
part of
ISSN 1756-8919
979
Editorial de Melo, Chin & dos Santos approved by the US FDA to treat SCD. In vivo, HU is metabolized to NO, which induces the expression of the γ-globin gene (HbG1 and HbG2) and fetal hemoglobin (HbF). HbF does not participate in the polymerization of hemoglobin and its elevation (>20%) is associated with fewer negative clinical symptoms and reduced early mortality in SCD patients. However, HU causes myelosuppression and stimulates the production of some proinflammatory cytokines, aggravating SCD symptoms. Moreover, many patients fail to respond to HU treatment, justifying the search for new drugs [6,7] . The strategies currently used to identify new drugs for the treatment of SCD symptoms focus on diseasemodifying molecules that: induce γ-globin expression and HbF synthesis; modify HbF by binding covalently to it; prevent hemoglobin dehydration; reduce iron overload by chelation; modify the rheological properties of blood; increase NO levels; inhibit Rho-kinase; or act as adenosine agonists [7] . Curative strategies, such as gene therapy and stem cell transplantation, present several challenges that must be overcome before their use in the future. Since the initial phenomenon in the development of SCD is the polymerization of HbS, we would like to focus on promising emergent therapies directed towards this stage of the disease. Current strategies to increase NO levels and to control the chronic inflammatory process of SCD offer novel options for drug discovery.
“
The lack of interest by the pharmaceutical industry and the paucity of specific treatments for sickle cell disease are among the harshest aspects of this disease.
”
HbS polymerization depends upon the intracellular concentration of HbS. The removal of potassium ions promotes the removal of chloride ions and water, causing an osmotic imbalance and the dehydration of RBCs. Reduced hydration of the erythrocyte facilitates contact between HbS molecules and promotes their polymerization. Therefore, the prevention of cellular dehydration by inhibiting the calcium-activated potassium–calcium cotransport channel (Gardos channel) has been examined as a potential therapeutic strategy. Examples of Gardos channel inhibitors include clotrimazole and senicapoc [8] . Another strategy is based on increasing HbF. Increased levels of HbF are related to less severe SCD symptoms, so the search for new molecules with this activity remains one of the most promising strategies for therapeutic drug design. Cytotoxic agents (i.e., HU), nucleoside analogs with inhibitory effects on DNA methyltransferases (e.g., 5-azacytidine,
980
Future Med. Chem. (2014) 6(9)
decitabine), histone deacetylase inhibitors (e.g., butyric acid and its derivatives) and thalidomide and its analogs (e.g., pomalidomide and lenalidomide) are some examples of HbF inducers.
“...[regadenoson] reduces the activation of
invariant natural killer T cells with no toxic effects, and, therefore, represents a promising treatment for sickle cell anemia.
”
After birth, the methylation of the γ-globin gene by DNA methyltransferase silences this gene, reducing HbF synthesis. 5-azacytidine and decitabine inhibit this enzyme and, thus, increase HbF production. However, as 5-azacytidine is toxic, only decitabine is used clinically as an alternative for patients who do not respond to treatment with HU [9] . Histone deacetylase inhibitors, such as butyric acid and its derivatives, increase the levels of histone acetylation and affect the transcription rate of the γ-globin gene, increasing HbF synthesis. Despite their in vitro and in vivo activities, the major limitations of these molecules are their inappropriate pharmacokinetic profiles (low absorption and short half-lives) and the lack of response after long-term therapy [7,10] . The exception is 2,2-dimethylbutyrate, which demonstrated adequate oral bioavailability and the capacity to induce HbF synthesis as a long-term therapy (26 weeks) in a Phase IIa trial [11] . Thalidomide and its analogs such as pomalidomide and lenalidomide, can induce γ-globin mRNA expression in a dose-dependent manner and stimulate HbF synthesis in vitro and in vivo in transgenic sickle cell mice. It has been proposed that thalidomide induces the expression of the γ-globin gene by increasing reactive oxygen species-mediated p38 MAPK signaling and histone H4 acetylation in adult erythropoiesis [12] . Pomalidomide induces HbF more potently compared with lenalidomide. Specifically, pomalidomide seems to regulate HbF by modifying the chromatin structure by acetylating histone H3 [13] . Thalidomide and its analogs also inhibit proinflammatory cytokines and display important analgesic/anti-inflammatory activities. These activities are useful in the treatment of SCD symptoms, as acute pain is the most common complication from the patient’s perspective, with a prevalence in more than 95% of patients [14] . Using a molecular modification approach, we have developed some hybrid compounds from thalidomide and NO donors (organic nitrate esters and furoxan subunits). Thalidomide–organic nitrate esters and thalidomide–furoxan hybrids released different levels of NO and stimulated HbF synthesis. The hybrid compounds also reduced the levels of proinflammatory cytokines, including TNF-α, in sickle cell mice and caused no mutations
future science group
What are the most promising emerging therapies for sickle cell disease?
in vitro or in vivo [15] . Furoxan derivatives demonstrated higher NO-donating ability and HbF-inducing effects than the organic nitrate esters [16] . There was a direct relationship between the release of NO and the stimulation of HbF synthesis. Future perspective Recently, the use of another two new classes of molecules as SCD treatments has been proposed: rhokinase inhibitors and adenosine agonists. The rhokinase protein is involved in several cellular processes, including contractility, chemotaxis, cellular adhesion and migration. Hydroxyfasudil is an inhibitor of rhokinase and shows promise in the treatment of SCD as it increases the levels of endothelial NO synthase, NO and cyclic guanosine monophosphate, thus inducing HbF production. Hydroxyfasudil reduces the levels of proinflammatory cytokines, such as IL-1β and TNF-α, and the levels of adhesion molecules (ICAM-1). This drug has demonstrated better activity than HU in reducing vaso-occlusion and inflammation [17] . Agonists of A2 adenosine have shown promising results in reducing the activation of invariReferences 1
2
dos Santos JL, Lanaro C, Chin CM. Advances in sickle cell disease treatment: from drug discovery until the patient monitoring. Cardiovasc. Hematol. Agents Med. Chem. 9(2), 113–127 (2011). Derebail VK, Nachman PH, Key NS, Ansede H, Falk RJ, Kshirsagar AV. High Prevalence of sickle cell trait in African Americans with ESRD. J. Am. Soc. Nephrol. 21(3), 413–417 (2010).
3
Manwani D, Frenette PS. Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. Blood 122(24), 3892–3898 (2013).
4
Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet 376(9757), 2018–2031 (2010).
5
Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. 1910. Yale J. Biol. Med. 74(3), 179–184 (2001).
6
Powars DR, Weiss JN, Chan LS, Schroeder WA. Is there a threshold level of fetal hemoglobin that ameliorates morbidity in sickle cell anemia? Blood 63(4), 921–926 (1984).
7
dos Santos JL, Chin CM. Recent insights on the medicinal chemistry of sickle cell disease. Curr. Med. Chem. 18(15), 2339–2358 (2011).
8
Ataga KI, Reid M, Ballas SK; ICA-17043-17010 Study Investigators et al. Improvements in haemolysis and indicators of erythrocyte survival do not correlate with acute vaso-occlusive crises in patients with sickle cell disease: a Phase III randomized, placebo-controlled, double-blind study of the Gardos channel blocker senicapoc (ICA-17043). Br. J. Haematol. 153(1), 92–104 (2011).
future science group
Editorial
ant natural killer T (iNKT) cells, leukocytes and platelet cells, thus reducing lung injury. There is also some evidence that iNKT cells are responsible for the propagation of the inflammatory lesions caused by the ischemia–reperfusion involved in the pathophysiology of sickle cell anemia, thus increasing inflammation and contributing to vascular occlusion. Regadenoson is a selective A 2 adenosine agonist and its use to treat sickle cell anemia is under investigation in clinical studies. The preliminary results have shown that this drug reduces the activation of iNKT cells with no toxic effects, and, therefore, represents a promising treatment for sickle cell anemia [18] . Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. 9
Saunthararajah Y, Molokie R, Saraf S et al. Clinical effectiveness of decitabine in severe sickle cell disease. Br. J. Haematol. 141(1), 126–129 (2008).
10
Resar LM, Segal JB, Fitzpatric LK, Friedmann A, Brusilow SW, Dover GJ. Induction of fetal hemoglobin synthesis in children with sickle cell anemia on low-dose oral sodium phenylbutyrate therapy. J. Pediat. Hematol. Oncol. 24(9), 737–741 (2002).
11
Kutlar A, Reid ME, Inati A et al. A dose-escalation Phase IIa study of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease. Am. J. Hematol. 88(11), 255–260 (2013).
12
Aerbajinai W, Zhu J, Gao Z, Chin K, Rodgers GP. Thalidomide induces gamma-globin gene expression through increased reactive oxygen species-mediated p38 MAPK signaling and histone H4 acetylation in adult erythropoiesis. Blood 110(8), 2864–2871 (2007).
13
Moutouh-de-Parseval LA, Verhelle D, Glezer E et al. Pomalidomide and lenalidomide regulate erythopoiesis and fetal hemoglobin production in human CD34 + cells. J. Clin. Invest. 118(1), 248–258 (2008).
14
Vandy Black L, Smith WR. Evidence-based mini-review: are systemic corticosteroids an effective treatment for acute pain in sickle cell disease? Hematology Am. Soc. Hematol. Educ. Program. 416−417 (2010).
15
Dos Santos JL, Lanaro C, Lima LM et al. Design, synthesis, and pharmacological evaluation of novel hybrid compounds to treat sickle cell disease symptoms. J. Med. Chem. 54(16), 5811–5819 (2011).
16
Dos Santos JL, Lanaro C, Chelucci RC et al. Design, synthesis, and pharmacological evaluation of novel hybrid compounds to treat sickle cell disease symptoms. Part II:
www.future-science.com
981
Editorial de Melo, Chin & dos Santos furoxan derivatives. J. Med. Chem. 55(17), 7583–7592 (2012). 17
982
Essack M, Radovanovic A, Bajic VB. Information exploration system for sickle cell disease and repurposing of hydroxyfasudil. PLoS ONE 8(6), e65190 (2013).
Future Med. Chem. (2014) 6(9)
18
Field JJ, Lin G, Okam MM et al. Sickle cell vaso-occlusion causes activation of iNKT cells that is decreased by the adenosine A2A receptor agonist regadenoson. Blood 121(17), 3329–3334 (2013).
future science group
Editorial Special Focus Issue: Rare Diseases
For reprint orders, please contact [email protected]
Medicinal Chemistry
What are the most promising emerging therapies for sickle cell disease? “Regadenoson is a selective A
adenosine agonist and its use to treat sickle cell 2 anemia is under investigation in clinical studies.
”
Keywords: fetal hemoglobin inducers • inflammation • new drugs • nitric oxide • sickle cell disease • vaso-occlusion
Sickle cell disease (SCD) is a chronic hereditary hemolytic anemia characterized by a single nucleotide mutation (GTG to GAG) in the sixth codon of the gene encoding β-globin, causing the replacement of glutamic acid with a valine residue in the protein forming the β-globin chain. Chronic inflammation, vasculopathy, microvascular vaso-occlusion and acute/chronic multi organ damage contribute to the main clinical symptoms of SCD [1] . The disease originated approximately 50,000–100,000 years ago in the countries of central and western Africa, India and east Asia. However, it has since spread worldwide as a result of slave trafficking in past centuries and racial intermixing. SCD is one of the most common hereditary hemoglobinopathies, affecting more than 60,000 homozygous African–American individuals and approximately 250,000 newborns annually throughout the world [2] . In environments of low oxygen tension, the substitution of glutamic acid (βGlu6) with valine (βVal6) in the β-chain of hemoglobin exposes the hydrophobic residues that induce the polymerization of hemoglobin S (HbS) molecules. The mutant polymers alter the cytoskeletal structure of red blood cells (RBCs), generating sickle-like cells. The polymeric fibers also damage the RBC membrane, causing hemolysis and reducing the numbers of RBCs, causing anemia in the affected individuals. RBC hemolysis is followed by the extravasation of the cellular contents, including hemoglobin and arginase. Arginase reduces the concentra-
10.4155/FMC.14.55 © 2014 Future Science Ltd
tion of arginine, which is used by endothelial NO synthase to produce NO. The heme group present in the released hemoglobin can also sequester endothelial NO, contributing to a ‘vasoconstriction’ phenotype in SCD patients. These low levels of NO also contribute to vaso-occlusion. This process is characterized by a strong interaction between RBCs, white blood cells and platelets, which also interact with the vascular endothelium since the expression of adhesion molecules is increased in vessel. These heterocellular aggregates then obstruct blood flow, leading to hypoxia in the adjacent vasculature. The injury to the vascular endothelium caused by sickle cell aggregates and the involvement of white blood cells in the vasoocclusion process increase the levels of pro inflammatory cytokines and contribute to the chronic inflammation in SCD patients. Vaso-occlusion is responsible for the main clinical events of SCD, which include retinopathy, acute chest syndrome, pulmonary hypertension, priapism, stroke, splenic sequestration, pain and splenic infarction [3,4] . Little progress has been made in the development of pharmacotherapies for SCD since its first description in 1910 by James Herrick, who observed anomalous sickle-shaped RBCs in a patient with severe anemia [5] . The lack of interest by the pharmaceutical industry and the paucity of specific treatments for SCD are among the harshest aspects of this disease. Today, hydroxyurea (HU), a ribonucleotide reductase inhibitor, is the only drug
Future Med. Chem. (2014) 6(9), 979–982
Thais Regina Ferreira de Melo Laboratório de Pesquisa e Desenvolvimento de Fármacos, Departamento de Fármacos e Medicamentos, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista–UNESP, Rodovia Araraquara Jaú Km 01, 14801-902, Araraquara, São Paulo, Brasil
Chung Man Chin Laboratório de Pesquisa e Desenvolvimento de Fármacos, Departamento de Fármacos e Medicamentos, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista–UNESP, Rodovia Araraquara Jaú Km 01, 14801-902, Araraquara, São Paulo, Brasil
Jean Leandro dos Santos Author for correspondence: Laboratório de Pesquisa e Desenvolvimento de Fármacos, Departamento de Fármacos e Medicamentos, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista–UNESP, Rodovia Araraquara Jaú Km 01, 14801-902, Araraquara, São Paulo, Brasil Tel.: +55 16 33016972 Fax: +55 16 33016960 [email protected]
part of
ISSN 1756-8919
979
Editorial de Melo, Chin & dos Santos approved by the US FDA to treat SCD. In vivo, HU is metabolized to NO, which induces the expression of the γ-globin gene (HbG1 and HbG2) and fetal hemoglobin (HbF). HbF does not participate in the polymerization of hemoglobin and its elevation (>20%) is associated with fewer negative clinical symptoms and reduced early mortality in SCD patients. However, HU causes myelosuppression and stimulates the production of some proinflammatory cytokines, aggravating SCD symptoms. Moreover, many patients fail to respond to HU treatment, justifying the search for new drugs [6,7] . The strategies currently used to identify new drugs for the treatment of SCD symptoms focus on diseasemodifying molecules that: induce γ-globin expression and HbF synthesis; modify HbF by binding covalently to it; prevent hemoglobin dehydration; reduce iron overload by chelation; modify the rheological properties of blood; increase NO levels; inhibit Rho-kinase; or act as adenosine agonists [7] . Curative strategies, such as gene therapy and stem cell transplantation, present several challenges that must be overcome before their use in the future. Since the initial phenomenon in the development of SCD is the polymerization of HbS, we would like to focus on promising emergent therapies directed towards this stage of the disease. Current strategies to increase NO levels and to control the chronic inflammatory process of SCD offer novel options for drug discovery.
“
The lack of interest by the pharmaceutical industry and the paucity of specific treatments for sickle cell disease are among the harshest aspects of this disease.
”
HbS polymerization depends upon the intracellular concentration of HbS. The removal of potassium ions promotes the removal of chloride ions and water, causing an osmotic imbalance and the dehydration of RBCs. Reduced hydration of the erythrocyte facilitates contact between HbS molecules and promotes their polymerization. Therefore, the prevention of cellular dehydration by inhibiting the calcium-activated potassium–calcium cotransport channel (Gardos channel) has been examined as a potential therapeutic strategy. Examples of Gardos channel inhibitors include clotrimazole and senicapoc [8] . Another strategy is based on increasing HbF. Increased levels of HbF are related to less severe SCD symptoms, so the search for new molecules with this activity remains one of the most promising strategies for therapeutic drug design. Cytotoxic agents (i.e., HU), nucleoside analogs with inhibitory effects on DNA methyltransferases (e.g., 5-azacytidine,
980
Future Med. Chem. (2014) 6(9)
decitabine), histone deacetylase inhibitors (e.g., butyric acid and its derivatives) and thalidomide and its analogs (e.g., pomalidomide and lenalidomide) are some examples of HbF inducers.
“...[regadenoson] reduces the activation of
invariant natural killer T cells with no toxic effects, and, therefore, represents a promising treatment for sickle cell anemia.
”
After birth, the methylation of the γ-globin gene by DNA methyltransferase silences this gene, reducing HbF synthesis. 5-azacytidine and decitabine inhibit this enzyme and, thus, increase HbF production. However, as 5-azacytidine is toxic, only decitabine is used clinically as an alternative for patients who do not respond to treatment with HU [9] . Histone deacetylase inhibitors, such as butyric acid and its derivatives, increase the levels of histone acetylation and affect the transcription rate of the γ-globin gene, increasing HbF synthesis. Despite their in vitro and in vivo activities, the major limitations of these molecules are their inappropriate pharmacokinetic profiles (low absorption and short half-lives) and the lack of response after long-term therapy [7,10] . The exception is 2,2-dimethylbutyrate, which demonstrated adequate oral bioavailability and the capacity to induce HbF synthesis as a long-term therapy (26 weeks) in a Phase IIa trial [11] . Thalidomide and its analogs such as pomalidomide and lenalidomide, can induce γ-globin mRNA expression in a dose-dependent manner and stimulate HbF synthesis in vitro and in vivo in transgenic sickle cell mice. It has been proposed that thalidomide induces the expression of the γ-globin gene by increasing reactive oxygen species-mediated p38 MAPK signaling and histone H4 acetylation in adult erythropoiesis [12] . Pomalidomide induces HbF more potently compared with lenalidomide. Specifically, pomalidomide seems to regulate HbF by modifying the chromatin structure by acetylating histone H3 [13] . Thalidomide and its analogs also inhibit proinflammatory cytokines and display important analgesic/anti-inflammatory activities. These activities are useful in the treatment of SCD symptoms, as acute pain is the most common complication from the patient’s perspective, with a prevalence in more than 95% of patients [14] . Using a molecular modification approach, we have developed some hybrid compounds from thalidomide and NO donors (organic nitrate esters and furoxan subunits). Thalidomide–organic nitrate esters and thalidomide–furoxan hybrids released different levels of NO and stimulated HbF synthesis. The hybrid compounds also reduced the levels of proinflammatory cytokines, including TNF-α, in sickle cell mice and caused no mutations
future science group
What are the most promising emerging therapies for sickle cell disease?
in vitro or in vivo [15] . Furoxan derivatives demonstrated higher NO-donating ability and HbF-inducing effects than the organic nitrate esters [16] . There was a direct relationship between the release of NO and the stimulation of HbF synthesis. Future perspective Recently, the use of another two new classes of molecules as SCD treatments has been proposed: rhokinase inhibitors and adenosine agonists. The rhokinase protein is involved in several cellular processes, including contractility, chemotaxis, cellular adhesion and migration. Hydroxyfasudil is an inhibitor of rhokinase and shows promise in the treatment of SCD as it increases the levels of endothelial NO synthase, NO and cyclic guanosine monophosphate, thus inducing HbF production. Hydroxyfasudil reduces the levels of proinflammatory cytokines, such as IL-1β and TNF-α, and the levels of adhesion molecules (ICAM-1). This drug has demonstrated better activity than HU in reducing vaso-occlusion and inflammation [17] . Agonists of A2 adenosine have shown promising results in reducing the activation of invariReferences 1
2
dos Santos JL, Lanaro C, Chin CM. Advances in sickle cell disease treatment: from drug discovery until the patient monitoring. Cardiovasc. Hematol. Agents Med. Chem. 9(2), 113–127 (2011). Derebail VK, Nachman PH, Key NS, Ansede H, Falk RJ, Kshirsagar AV. High Prevalence of sickle cell trait in African Americans with ESRD. J. Am. Soc. Nephrol. 21(3), 413–417 (2010).
3
Manwani D, Frenette PS. Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. Blood 122(24), 3892–3898 (2013).
4
Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet 376(9757), 2018–2031 (2010).
5
Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. 1910. Yale J. Biol. Med. 74(3), 179–184 (2001).
6
Powars DR, Weiss JN, Chan LS, Schroeder WA. Is there a threshold level of fetal hemoglobin that ameliorates morbidity in sickle cell anemia? Blood 63(4), 921–926 (1984).
7
dos Santos JL, Chin CM. Recent insights on the medicinal chemistry of sickle cell disease. Curr. Med. Chem. 18(15), 2339–2358 (2011).
8
Ataga KI, Reid M, Ballas SK; ICA-17043-17010 Study Investigators et al. Improvements in haemolysis and indicators of erythrocyte survival do not correlate with acute vaso-occlusive crises in patients with sickle cell disease: a Phase III randomized, placebo-controlled, double-blind study of the Gardos channel blocker senicapoc (ICA-17043). Br. J. Haematol. 153(1), 92–104 (2011).
future science group
Editorial
ant natural killer T (iNKT) cells, leukocytes and platelet cells, thus reducing lung injury. There is also some evidence that iNKT cells are responsible for the propagation of the inflammatory lesions caused by the ischemia–reperfusion involved in the pathophysiology of sickle cell anemia, thus increasing inflammation and contributing to vascular occlusion. Regadenoson is a selective A 2 adenosine agonist and its use to treat sickle cell anemia is under investigation in clinical studies. The preliminary results have shown that this drug reduces the activation of iNKT cells with no toxic effects, and, therefore, represents a promising treatment for sickle cell anemia [18] . Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. 9
Saunthararajah Y, Molokie R, Saraf S et al. Clinical effectiveness of decitabine in severe sickle cell disease. Br. J. Haematol. 141(1), 126–129 (2008).
10
Resar LM, Segal JB, Fitzpatric LK, Friedmann A, Brusilow SW, Dover GJ. Induction of fetal hemoglobin synthesis in children with sickle cell anemia on low-dose oral sodium phenylbutyrate therapy. J. Pediat. Hematol. Oncol. 24(9), 737–741 (2002).
11
Kutlar A, Reid ME, Inati A et al. A dose-escalation Phase IIa study of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease. Am. J. Hematol. 88(11), 255–260 (2013).
12
Aerbajinai W, Zhu J, Gao Z, Chin K, Rodgers GP. Thalidomide induces gamma-globin gene expression through increased reactive oxygen species-mediated p38 MAPK signaling and histone H4 acetylation in adult erythropoiesis. Blood 110(8), 2864–2871 (2007).
13
Moutouh-de-Parseval LA, Verhelle D, Glezer E et al. Pomalidomide and lenalidomide regulate erythopoiesis and fetal hemoglobin production in human CD34 + cells. J. Clin. Invest. 118(1), 248–258 (2008).
14
Vandy Black L, Smith WR. Evidence-based mini-review: are systemic corticosteroids an effective treatment for acute pain in sickle cell disease? Hematology Am. Soc. Hematol. Educ. Program. 416−417 (2010).
15
Dos Santos JL, Lanaro C, Lima LM et al. Design, synthesis, and pharmacological evaluation of novel hybrid compounds to treat sickle cell disease symptoms. J. Med. Chem. 54(16), 5811–5819 (2011).
16
Dos Santos JL, Lanaro C, Chelucci RC et al. Design, synthesis, and pharmacological evaluation of novel hybrid compounds to treat sickle cell disease symptoms. Part II:
www.future-science.com
981
Editorial de Melo, Chin & dos Santos furoxan derivatives. J. Med. Chem. 55(17), 7583–7592 (2012). 17
982
Essack M, Radovanovic A, Bajic VB. Information exploration system for sickle cell disease and repurposing of hydroxyfasudil. PLoS ONE 8(6), e65190 (2013).
Future Med. Chem. (2014) 6(9)
18
Field JJ, Lin G, Okam MM et al. Sickle cell vaso-occlusion causes activation of iNKT cells that is decreased by the adenosine A2A receptor agonist regadenoson. Blood 121(17), 3329–3334 (2013).
future science group
