Drug Repurposing in Sickle Cell Disease: Evaluating Imatinib as a Therapeutic Candidate

Drug Repurposing in Sickle Cell Disease: Evaluating Imatinib as a Therapeutic Candidate | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 19 August 2025 V1 Latest version Share on Drug Repurposing in Sickle Cell Disease: Evaluating Imatinib as a Therapeutic Candidate Authors : bijan keikhaei , Daryush Purrahman 0000-0002-8215-2686 , Najmeh Nameh Goshay Fard , Elham Abedi , Farnoush Farokhian 0009-0001-8108-9259 , and Reyhane Khademi [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.175562135.50163879/v1 425 views 196 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Sickle cell disease (SCD) is an inherited hemolytic hemoglobinopathy characterized by a wide range of complications, including chronic hemolysis, painful Vaso-occlusive crises, and progressive organ damage. At present, one of the main therapeutic options prescribed for patients with SCD is hydroxyurea capsules, often in combination with various analgesics. However, this therapeutic approach may fail to provide adequate relief during active disease episodes, particularly when severe pain crises occur. Drug repurposing has emerged as a promising strategy in situations where de novo drug development is limited or not feasible, thereby addressing existing therapeutic gaps. Compared with traditional drug development procedures, this strategy offers advantages such as reduced costs and accelerated timelines for drug discovery. Imatinib (Gleevec), which is primarily indicated as part of standard chemotherapy for patients with chronic myeloid leukemia (CML), has been considered for repurposing in SCD. Based on its known mechanisms of action, this narrative review provides a theoretical assessment of the potential applications of imatinib in SCD. Examination of the molecular pathways shared between imatinib’s targets and the pathogenesis of SCD has yielded controversial findings: some studies suggest imatinib may reduce hemolysis and alleviate pain crises, while others have not supported such benefits. Direct investigations of imatinib in the context of SCD are limited, yet available evidence has reported potentially valuable outcomes, including decreased hospitalization rates, shorter hospital durations, and reduced organ damage. Current evidence remains insufficient for definitive conclusions, underscoring the need for well-designed clinical and translational studies to clarify the feasibility of incorporating imatinib into SCD management. Drug Repurposing in Sickle Cell Disease: Evaluating Imatinib as a Therapeutic Candidate Bijan Keikhaei a , Daryush Purrahman a , Najmeh Nameh Goshay Fard a , Elham Abedi b , Farnoush Farokhian b , Reyhane Khademi a* a Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. b Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Running title: Imatinib in Sickle cell disease Abstract Sickle cell disease (SCD) is an inherited hemolytic hemoglobinopathy characterized by a wide range of complications, including chronic hemolysis, painful Vaso-occlusive crises, and progressive organ damage. At present, one of the main therapeutic options prescribed for patients with SCD is hydroxyurea capsules, often in combination with various analgesics. However, this therapeutic approach may fail to provide adequate relief during active disease episodes, particularly when severe pain crises occur. Drug repurposing has emerged as a promising strategy in situations where de novo drug development is limited or not feasible, thereby addressing existing therapeutic gaps. Compared with traditional drug development procedures, this strategy offers advantages such as reduced costs and accelerated timelines for drug discovery. Imatinib (Gleevec), which is primarily indicated as part of standard chemotherapy for patients with chronic myeloid leukemia (CML), has been considered for repurposing in SCD. Based on its known mechanisms of action, this narrative review provides a theoretical assessment of the potential applications of imatinib in SCD. Examination of the molecular pathways shared between imatinib’s targets and the pathogenesis of SCD has yielded controversial findings: some studies suggest imatinib may reduce hemolysis and alleviate pain crises, while others have not supported such benefits. Direct investigations of imatinib in the context of SCD are limited, yet available evidence has reported potentially valuable outcomes, including decreased hospitalization rates, shorter hospital durations, and reduced organ damage. Current evidence remains insufficient for definitive conclusions, underscoring the need for well-designed clinical and translational studies to clarify the feasibility of incorporating imatinib into SCD management. Keywords: Sickle cell disease, Imatinib, Drug repurposing, Management, Pain crisis. Highlights • Theoretical application of imatinib in addressing challenges observed in the pathogenesis of SCD has yielded controversial findings. • Clinical data on drug repurposing of imatinib in SCD suggest promising potential, particularly in reducing the number and duration of hospitalizations. • The drug repurposing pathway of imatinib in SCD is still in its early stages and may not necessarily lead to a definitive outcome. • Imatinib use is not recommended in SCD patients with thrombocytopenia or those of reproductive age. • Adverse effects may occur; therapy should be discontinued and medical advice sought promptly. Introduction Sickle cell anemia (SCA) is one of the most prevalent hemoglobinopathies and among the most severe inherited disorders, imposing a considerable burden on healthcare systems(1). The disease results from a genetic mutation in codon 6 of the β-globin gene, where substitution of valine (GTG) for glutamic acid (GAG) leads to the production of a hemoglobin variant known as HbS. Red blood cells containing HbS are highly prone to hemolysis, and chronic hemolysis represents one of the earliest clinical consequences of this genetic mutation(2). However, the clinical manifestations observed in patients extend far beyond anemia alone. The condition encompasses a spectrum of unpredictable symptoms with varying severity, often involving multiple organ systems, thereby creating complex cases with challenging management. In such instances, the broader term sickle cell disease (SCD) is applied. Prominent clinical features of SCD include anemia, acute pain crises, acute chest syndrome, and progressive organ failure(3). Hydroxyurea (HU), originally developed as an anticancer drug, is now a standard therapy for SCD, primarily prescribed to increase fetal hemoglobin (HbF), a favorable prognostic marker in this condition(4). In addition, hydroxyurea has been shown to reduce both the frequency and severity of painful crises. However, its beneficial effects may not be consistent, as the therapeutic response varies among patients, and some individuals may even develop resistance to HU(5). Beyond hydroxyurea, the main therapeutic options for alleviating pain crises in SCD include fluid therapy, supplemental oxygen, and analgesics(6). In cases of severe pain, opioid administration may be required. Nevertheless, opioid use should be approached with caution: first, because their long-term side effects are not fully characterized, and second, because some patients may require high doses of chronic opioids, which can lead to tolerance or even dependence, creating secondary challenges in management(7). In recent years, the introduction of new agents—such as the oral anti-sickling drug Voxelotor and the injectable monoclonal antibody against P-selectin, crizanlizumab—has partially addressed therapeutic needs in SCD, including improvements in hemoglobin levels(8, 9). Despite their approval, Crizanlizumab and Voxelotor are costly, show only modest efficacy, and remain largely inaccessible in low-resource countries(10, 11). Drug repurposing—also known as drug repositioning—is the process of discovering new clinical applications for approved drugs or drug candidates beyond their original indication(12). In other words, when an urgent therapy is required for a disease, or when the development of conventional drugs proves to be cost-inefficient, drug repurposing becomes a strategy of choice(13). Considering that therapeutic strategies developed for SCD have yet to achieve consistently high success rates, drug repurposing may serve as a viable approach(14). In this narrative review, we first evaluate the theoretical pathways through which imatinib may intervene within the pathogenic network of SCD, thereby identifying potential targets for its repurposing. We then summarize the available clinical and experimental evidence regarding the application of imatinib in the context of SCD. Imatinib: background and pharmacological profile Imatinib (molecular formula C₂₉H₃₁N₇O·CH₄SO₃, molecular mass 589.7 g/mol) is a tyrosine kinase inhibitor (TKI) that was introduced in May 2001 under the trade name Gleevec®, and subsequently received FDA approval as standard front-line therapy for the treatment of adult patients with chronic myeloid leukemia (CML)(15). The development of imatinib began with modifications of the original 2-phenylaminopyrimidine lead compound, which was further optimized by adding methyl and pyridyl groups, thereby enhancing both its selectivity and inhibitory potency against kinases. Additionally, incorporation of an N-methyl-piperazine moiety improved its aqueous solubility and oral bioavailability(16). Imatinib targets a substantial number of tyrosine kinases, including mutated forms (such as BCR-ABL) and wild-type kinases (c-Abl, PDGFR, c-Kit, c-Src, Lck), underscoring its potential activity in both transformed and non-transformed cells(17). Beyond tyrosine kinases, imatinib also inhibits several non-tyrosine kinase proteins, such as quinone oxidoreductase-2, the ATP-sensitive potassium (K⁺) channel, and vacuolar-type H⁺-ATPase (V-ATPase)(18). Owing to this diverse spectrum of action, imatinib—although primarily indicated for CML—has been investigated in various off-target clinical settings, including renal diseases, gastrointestinal stromal tumors (GISTs), and even COVID-19 (Table 1). For example, a report on a modest number of patients with both CML and type 2 diabetes demonstrated that imatinib provided therapeutic benefits not only for leukemia but also for diabetes management(19, 20). Similarly, studies in animal models and cell lines have shown that imatinib can protect pancreatic islet β-cells from apoptosis by suppressing inflammatory mediators, while also enhancing β-cell function through diminished JNK phosphorylation(21, 22). Together, these findings suggest a potential role for imatinib in diabetes treatment. Such mechanisms are regarded as off-target effects, which provide the rationale for considering imatinib within the framework of drug repurposing Imatinib also possesses several favorable characteristics that enhance its clinical utility. First, it is generally well tolerated and can be readily dissolved in water, making it particularly suitable for sensitive patient groups such as those with swallowing difficulties. Second, the majority of imatinib-associated adverse effects (AEs) are of mild to moderate severity. AEs are typically categorized as hematologic or non-hematologic. Reported hematologic events include variable degrees of cytopenias, while the most common overall side effect is edema, which can be managed with diuretic therapy, dose reduction, or drug discontinuation(23). Cutaneous reactions such as maculopapular eruptions have also been reported in some patients receiving imatinib(24). Other AEs may include muscle cramps, musculoskeletal pain, fatigue, insomnia, diarrhea, weight gain, growth retardation, and night sweats(25). On the other hand, a subset of patients develops resistance to imatinib, defined as either a lack of therapeutic response or loss of a previously achieved response(26). Table 1 . Evidence for Imatinib in Alternative Therapeutic Applications COVID-19 RCT 168 hospitalized COVID-19 patients Imatinib exposure increased (↑AAG), but higher CT trough showed no clinical benefit and was linked to worse oxygenation, P/F ratio, and WHO score. (27) RCT 385 hospitalized hypoxemic COVID-19 patients Imatinib showed no ↑ cardiac risk; safe in patients with QTc 40% (28) RCT + Meta-analysis 156 hospitalized COVID-19 patients (Finland) + pooled trials Imatinib showed no significant short- or long-term benefit in mortality, recovery, QoL, or long COVID symptoms; pooled data suggest uncertain mortality benefit. (29) Cerebral ischemia In vivo Male Mongolian gerbils, imatinib pre-ischemia Imatinib improved neurological function, reduced hippocampal neuronal death, and attenuated ER stress; neuroprotective potential. (30) Reproductive health In vivo Adult female mice, daily imatinib (4–6 weeks) Imatinib ↓ Ovarian reserve & embryo quality; no impact on ovulation/fertilization. (31) In vivo Adult male Kunming mice; imatinib at various doses Imatinib crossed blood-testis barrier; ↓ sperm count/motility, ↑ deformity; dose-dependent fertility loss. (32) Chagas disease (Parasitic illness) In vitro + In silico T. cruzi bloodstream & intracellular forms Imatinib analogues: 7/8 more potent than benznidazole; LS2/89(one of analogues) was most effective. (33) In vitro + Combination study Multiple T. cruzi strains; L929 & murine cardiac cells Imatinib alone showed moderate activity; combination with benznidazole was additive; among 14 imatinib derivatives, one derivative matched potency but low selectivity. (34) Mesenchymal chondrosarcoma In vitro + In vivo MCS cell models + PDX model Imatinib showed strong cytotoxicity in vitro and ↓ tumor growth in PDX models (supports repurposing for MCS). (35) Diabetes Mellitus In vivo + In vitro NOD mice + pancreatic β-cell lines Imatinib modestly ↓ mitochondrial respiration, ↑ AMPK, ↓ TXNIP; protected β-cells from amyloid toxicity. (36) In vivo STZ-induced T1DM rats, oral imatinib (4 weeks) Imatinib Improved glycemia & insulin; preserved β-cell morphology; ↓ oxidative stress, inflammation, and apoptosis. (37) Acute Spinal Cord Injury In vivo Rodent SCI model, delayed imatinib (4–24 h) Delayed imatinib treatment improved locomotion/bladder, ↓ hypersensitivity; modulated macrophages; ↑ MCP-1, MIP-3α, IL-8 as potential biomarkers; reduced macrophage activation at spinal cord injury site. (38) Abbreviation. RCT: Randomized Controlled Trial, T. cruzi: Trypanosoma cruzi, MCS: Mesenchymal Chondrosarcoma, SCI: Spinal Cord Injury, PDX: Patient-Derived Xenografts, AAG1: Alpha-1 acid glycoprotein. not-yet-known not-yet-known not-yet-known unknown Rationale for repurposing imatinib in sickle cell disease In this section, we provide a theoretical assessment of imatinib’s efficacy in counteracting events analogous to those observed in the pathogenesis of SCD. Such an approach An error in the conversion from LaTeX to XML has occurred here. offers a rational framework for understanding the potential of imatinib as a drug repurposing candidate in SCD (Table 2). not-yet-known not-yet-known not-yet-known unknown Hemolysis Deoxygenation in RBCs containing HbS is associated with HbS polymerization, which transforms the cell shape from a flexible biconcave disc to a rigid, sickled form. Sickled RBCs become trapped within small vessels, leading to multiple complications that will be discussed later. Upon reoxygenation, polymerization is reversed, resulting in unsickling. Repeated cycles of sickling and unsickling progressively damage the RBC membrane, ultimately leading to irreversible changes and hemolysis(2). In addition to hypoxia, dehydration plays a critical role in both sickling and hemolysis of HbS-containing RBCs(39). On the membrane of sickling RBCs, a specific ion channel known as Psickle becomes activated, allowing an influx of Ca²⁺. Subsequent accumulation of intracellular Ca²⁺ activates the Gardos channel (encoded by KCNN4 ) on the RBC surface, leading to efflux of K⁺ and Cl⁻ (to maintain ionic homeostasis). Loss of K⁺ and Cl⁻ disrupts osmotic balance, resulting in water efflux, dehydration, and increased cell density, which promotes cellular shrinkage(40-42). Evidence from both in vivo and in vitro studies indicates that imatinib modulates intracellular calcium concentration in peripheral blood mononuclear cells from CML patients(43, 44). Although the precise mechanism by which imatinib mediates this effect is not fully understood, if a similar impact occurs in SCD, it could represent a strategy to reduce RBC dehydration and hemolysis (Figure 1). When HbS undergoes denaturation, its ability to retain heme within the hemoglobin structure is lost, leading to heme release into the cytoplasm and generation of intracellular oxidants such as reactive oxygen species (ROS)(45). ROS generated in this process impair cytoskeletal integrity and membrane stability by inducing Band 3 tyrosine phosphorylation, thereby promoting hemolysis(46). Imatinib, by inhibiting the tyrosine kinase Syk, has been shown to block Band 3 tyrosine phosphorylation, thereby preserving RBC integrity and preventing hemolysis(47). Furthermore, in rat models of ulcerative colitis, pre-treatment with imatinib was found to decrease malondialdehyde (MDA, a marker of oxidative stress) levels in colonic tissue, while successfully enhancing superoxide dismutase (SOD) activity and glutathione (GSH) levels (48). These findings suggest a potential antioxidant effect of imatinib that could mitigate hemolysis in SCD. However, in contrast to these results, some studies report that imatinib treatment in CML increases ROS levels. Additionally, cells resistant to imatinib have been found to express higher levels of the antioxidant enzyme catalase, highlighting the controversial nature of imatinib’s antioxidant potential(49). Figure 1 . Proposed effects of imatinib on RBC hemolysis in SCD. Figure legend: Imatinib may reduce Ca²⁺ influx, Gardos channel activation, and ROS-mediated cytoskeletal damage, while enhancing antioxidant defenses. Pain crisis Pain crisis is another major clinical manifestation observed in patients with SCD and is a key determinant of patients’ quality of life. Recurrent painful crises, particularly those occurring more than three times per year and requiring hospitalization, are associated with decreased survival in adults(50). It is now well established that Vaso-occlusion (VOC) represents a central event in the development of pain crises(51). arises from vascular obstruction involving a complex interplay between sickled RBCs, circulating immune cells, platelets, and vascular endothelial cells, collectively forming structures referred to as neutrophil extracellular traps (NETs)(52). NETs contribute both to pain crises and to ischemia–reperfusion injury in target tissues. Imatinib may influence VOC and its associated complications by modulating key components of NET formation. Platelets play a crucial role in SCD pathogenesis through secretion of growth factors such as PDGF and via their aggregatory capacity(53). However, data regarding platelet function and count in CML patients treated with imatinib remain controversial, as conflicting results have been reported in platelet aggregometry testing(54-56). If imatinib’s role in platelet dysfunction is confirmed, its use would be contraindicated in SCD patients with thrombocytopenia (e.g., TTP-like syndromes) (57, 58). In SCD, vascular endothelial cells are initially activated by elevated levels of hemoglobin and heme in the plasma. This activation upregulates adhesion receptors such as P-selectin, E-selectin, and vWF on the endothelial surface thereby facilitating the recruitment and adhesion of leukocytes, particularly neutrophils, at sites of VOC(59, 60). Evidence regarding imatinib’s effects on endothelial adhesion molecule expression remains inconclusive: while some studies suggest imatinib reduces their expression, others report no significant effect(61-64). Immune cells are key drivers of SCD pathogenesis. Their role becomes most evident in VOC and acute chest syndrome, where heightened activity often parallels disease severity.(65, 66). Plasma from SCD patients—particularly during VOC—shows markedly elevated GM-CSF levels, which may explain the leukocytosis observed in these individuals(67). Conversely, therapeutic use of G-CSF or GM-CSF has been associated with severe VOC and acute chest syndrome in SCD patients(68, 69). In CML, imatinib has been shown to reduce WBC counts through c-kit inhibition, leading to myelosuppression(70). Notably, c-kit expression decreases during hematopoietic differentiation and is primarily retained in immune cells, most prominently in mast cells(71). Supporting this, Cerny-Reiterer et al. demonstrated that imatinib suppresses both the number and function of mast cells in vitro and in vivo(72, 73). It is also plausible that imatinib exerts off-target effects on additional immune lineages, since mast cells account for only a small fraction of immune cells, and their suppression alone cannot explain the overall reduction in WBC count. Mast cells may represent a key target in SCD pathogenesis. Histamine, a mast cell–derived mediator, is significantly elevated in sickle mice and in patients during pain episodes(74-76). Moreover, plasma histamine levels in SCD patients show an inverse correlation with HbF levels(75). These findings suggest that imatinib-mediated mast cell inhibition could have dual benefits in SCD management by both enhancing HbF and alleviating pain. In this context, laboratory studies have shown that imatinib suppresses the release of mast cell mediators—including tryptase, substance P, and CGRP—from morphine-treated mast cells(77). These mediators are known contributors to morphine and NSAID tolerance(78). Consequently, imatinib may attenuate morphine tolerance by inhibiting mast cell activity. This mechanism could potentially explain reports of recurrent VOC following discontinuation of imatinib, where recurrence was not attributable to changes in WBC count, hemoglobin concentration, HbF levels, or hemolysis indices(70, 79). Furthermore, modulation of inflammatory pathways by imatinib, and their reactivation in its absence, may provide an additional explanation for these findings. Regulation of inflammatory signaling is another recognized property of imatinib. For instance, in malignancy models, imatinib has been shown to suppress NF-κB activation and reduce production of pro-inflammatory cytokines IL-8 and IL-6(43). In colitis models, imatinib inactivates JAK2 and STAT3 phosphorylation, attenuating upregulation of pro-inflammatory cytokines such as IL-6, IL-17, and IL-23(48, 80). Although SCD is classified as a hematologic disorder, it is increasingly recognized as a chronic sterile inflammatory disease, given the central role of inflammation in its pathophysiology(81). Notably, levels of inflammatory markers remain elevated not only during VOC but also after clinical recovery and even in the steady state(82). Pro-inflammatory cytokines, particularly IL-17, induce cyclooxygenase-2 (COX-2) activation in SCD. Activated COX-2 contributes to chronic pain and hyperalgesia while also promoting microvascular permeability through increased production of prostaglandin E2 (PGE2)(83, 84). Supporting this, Graido-Gonzalez et al. demonstrated significantly elevated plasma PGE2 levels in SCD patients during crises compared with healthy controls(85). COX-2 inhibition, such as with celecoxib, has been shown to reduce pain and inflammation, decrease opioid requirements, and shorten hospitalizations(86, 87). Reports on the effects of imatinib on COX-2 and PGE2 suggest potential therapeutic benefit in modulating these pathways. In ulcerative colitis models, imatinib suppressed COX-2 expression in male rats, though this effect may have been secondary to reduced IL-17 levels(48). Other studies report that imatinib attenuates pro-inflammatory cytokine release through interactions with PGE2(88). However, contradictory findings also exist, with some reports showing no suppression—or even increased activity—of COX-2 and PGE2 under imatinib treatment(88, 89). Therefore, the role of imatinib in modulating these pathways remains uncertain, and its potential in managing SCD-related complications through COX-2 and PGE2 suppression requires further investigation. Table 2 . Overview of Drug Candidates Repurposed for Hemoglobinopathies. Clotrimazole (CTL) Candidiasis Sickle cell disease Transgenic SAD1 mice; Oral CLT, 80→160 mg/kg/day Gardos channel blockade → ↓ K⁺/water loss, ↓ RBC dehydration, MCHC & density; ↑ RBC K⁺, hematocrit. Effects reversible; sustained with long-term CLT. (90) Human; 5 adult patients; Oral CTL, 10→30 mg/kg/day Gardos channel blockade → ↓ K⁺/water loss → ↓RBC dehydration; ↑ RBC K⁺, slight ↑ hemoglobin. Adverse effects : mild dysuria, reversible ↑ ALT/AST at 30 mg/kg/day. (91) Mithramycin (MTH) Neoplasms and Paget’s bone disease β-thalassemia Primary erythroid precursor cells from patients; MTH (dose not referred) Potent HbF inducer via dual mechanism: inhibits Sp1/KLF1-mediated BCL11A transcription & blocks BCL11A–γ-globin promoter binding. (92) Patient-derived erythroid precursors; 2-phase liquid culture with EPO (drug added day 4–5 of phase 2); MTH, 10→25 nM ↑ HbF in all tested patients; often superior to hydroxyurea; minimal erythroid growth inhibition at HbF-inducing doses. (93) Palbociclib Neoplasm β- Hemoglobinopathy Erythroid cells from transgenic murine fetal liver; Palbociclib 10→30 μM ↑ HbA₂ & HbF; no significant β-globin change; cytotoxic at 30 μM. (94) Nexturastat Neoplasms Erythroid cells from transgenic murine fetal liver; Nexturastat 10→30 μM ↑ HbA₂; no HbF activation; cytotoxic at 30 μM. (94) Pyridoxamine Vitamin B6 deficiency Sickle cell disease SCD mice and patient samples; Oral pyridoxamine, 10→100 mg/kg Improved microvascular flow & survival in SCD models; ↓ Vaso-occlusion; benefits enhanced with hydroxyurea. (95) Hydroxyurea SCA & Neoplasm HbE/β-thalassemia 49 transfusion-dependent Bengali patients; Hydroxyurea (dose not referred) 61% showed ↑ hemoglobin and longer transfusion-free interval; response linked to XmnI γ-globin polymorphism. (96) Cilostazol Intermittent claudication β- Hemoglobinopathy K562 cells, β-YAC mice; Cilostazol, 5→100 µM ↑ HbF via erythroid differentiation & γ-globin induction; minimal cytotoxicity; no β-globin change; superior to hydroxyurea at optimal dose. (97) Genistein Post- menopausal individuals Sickle cell disease SCD patient (in vitro assay); Genistein 20→100 × 10 6 M Inhibited HbS polymerization & sickling; ↑ erythrocyte fragility; proposed anti-sickling agent (98) TDT: transfusion-dependent β-thalassemia, SCD: Sickle cell disease, β-YAC mice: transgenic mice that carry a human β-globin gene cluster on a yeast artificial chromosome. Preclinical and clinical evidence of imatinib in sickle cell disease In this section, we review studies that have directly investigated the effects of imatinib in the context of SCD. One of the most important studies in this regard is a registered clinical trial (ID: NCT03997903) on clinicaltrials.gov , conducted by Seethal Jacob and colleagues in the United States. As of August 2025, this trial has been terminated, but no reliable results have yet been reported. The outcomes of this clinical trial could potentially address many of the existing questions and uncertainties regarding the use of imatinib in SCD and more precisely determine the therapeutic potential of this drug in this condition. A research group from Iran evaluated the number and duration of hospitalizations, along with hematological parameters, in SCD patients receiving imatinib, and compared these outcomes with a control group. Their assessment showed that both the number and duration of hospitalizations were reduced by approximately 16-fold in the imatinib-treated group, while no significant changes in hematological parameters were observed(99). It should be noted that hospitalization in SCD patients is most commonly due to painful crises. As discussed in the previous section, imatinib may alleviate pain in SCD patients through two mechanisms: interference with pain-generating pathways and reduction of tolerance to analgesic therapies. For instance, studies in an SCD mice model demonstrated that imatinib, by interfering with PDGFR activation, not only relieved chronic pain but also reduced the tolerance or need for high doses of analgesics such as morphine(100, 101). Accordingly, the demand for analgesics such as pethidine, tramadol, and NSAIDs was decreased in SCD patients treated with imatinib(99). Furthermore, a case report of a patient with concomitant SCD and CML indicated that imatinib therapy improved both the severity and recurrence of VOC (102). These clinical findings strongly suggest that imatinib is beneficial in mitigating painful crises in SCD. A group of investigators, using various experimental approaches, evaluated the effects of imatinib in SCD mice subjected to ischemia/reperfusion (I/R) injury. They found that inflammatory vasculopathy markers such as VCAM-1, E-selectin, and ET-1 were reduced under these conditions, which in turn was associated with decreased immune cell adhesion(11). This observation is assumed to be due to suppression of inflammation and downregulation of adhesion receptors on endothelial cells. Consistent with this, studies have demonstrated that imatinib attenuates immune cell infiltration at VOC sites and reduces the production of inflammatory mediators in these regions(74). The potential of imatinib in preventing organ damage and failure during the pathogenesis of SCD has also been investigated. For example, iron released from hemolyzed RBCs accumulates in organs such as the kidney and lung. Iron deposition directly damages tissues and also induces local inflammation(103). Researchers have shown that imatinib prevents hemosiderin deposition induced by hypoxia/reoxygenation (H/R) in macrophages, which are the only cells that accumulate iron in the lung, thereby protecting against pulmonary injury(11). Similarly, administration of imatinib in SCD mice reduced H/R-induced kidney damage(11). Imatinib appears to protect organs against injury by attenuating oxidative stress(11). In a similar approach, imatinib has been shown to reduce oxidative stress in streptozotocin-induced diabetic rats(37). Moreover, imatinib has demonstrated favorable effects in preventing fibrosis of the lung and kidney in SCD models. This effect is believed to be mediated by inhibition of the mammalian target of rapamycin (mTOR) pathway, which is a downstream signaling cascade of PDGFR(11) In addition, imatinib suppresses the profibrogenic activity of TGF-β, thereby inhibiting tissue fibrosis(104). In agreement with this finding, studies in kidneys of AA and SCD mice treated with imatinib revealed increased expression of miR-200a, a negative regulator of TGF-β1. This observation suggests that the reduction of TGF-β1, a key driver of fibrosis, may underlie the antifibrotic effects of imatinib in SCD(11). Conclusion and future directions In the present study, the potential applications of imatinib in addressing SCD-related complications have been discussed using different approaches. While theoretical pathway analyses provide considerable evidence supporting the potential benefit of imatinib in SCD, some controversial results have also been reported. In contrast, studies that have directly tested imatinib in the context of SCD (both clinical and experimental) present more consistent evidence regarding the utility of this drug repurposing approach. Nevertheless, several important unresolved questions remain, which should be carefully addressed in the design of future studies: 1. Comorbidities: Since SCD is a lifelong chronic disorder, how imatinib might be integrated into the management of complex conditions such as coexisting diabetes, viral infections (e.g., COVID-19), or pulmonary hypertension remains unclear. Recent experimental evidence in mice treated with imatinib has shown that the drug may reduce blood glucose levels through both a direct effect on PPARγ and an indirect anti-inflammatory mechanism, which could potentially benefit SCD patients with concomitant diabetes(105). However, no study has directly evaluated this issue in SCD. 2. HbF induction: As previously noted, HbF is a favorable prognostic factor in SCD pathogenesis. Reports on the ability of imatinib to induce HbF expression remain controversial(106, 107). Importantly, none of these data were generated in the context of SCD, highlighting the need for targeted investigation in this area. 3. Aplastic anemia risk: Imatinib has been associated with the development of aplastic anemia in isolated reports (X). Given this risk, the optimal safe and effective dose of imatinib for SCD remains to be determined. 4. Drug interactions: The safety of combining imatinib with hydroxyurea remains uncertain, and it is not known whether they should be co-administered or used separately. At present, no evidence is available on possible interactions with antibiotics or vaccines. 5. Alternative TKIs: Comparative studies are needed to evaluate alternative TKIs such as nilotinib in terms of efficacy and safety relative to imatinib in SCD(25). Key considerations of imatinib use in SCD should be carefully addressed to guide the design of future studies. One of the most critical points is that imatinib cannot be applied universally across all SCD patient groups. For example, in vivo mouse studies demonstrated that long-term imatinib administration in females depleted ovarian reserves and reduced embryo quality, although ovulation and fertilization were not affected. These findings suggest that women may maintain apparently normal ovulatory cycles under imatinib treatment but face reduced chances of achieving successful and healthy pregnancies in the future. Similarly, studies in male mice revealed various abnormalities in spermatogonia and an overall reduction in cell counts(32) (Table 2). Collectively, these findings indicate impairment of reproductive health, strongly contraindicating imatinib use in individuals of reproductive age. Additionally, some adverse events may arise from off-target effects of the drug. For example, a recent case report described imatinib-induced ulcerative colitis in a 56-year-old man, which developed approximately five years after treatment with imatinib at a dose of 400 mg/day. It should be emphasized that the first and most important management step in such adverse events is prompt discontinuation of therapy. In the reported case, discontinuation of imatinib along with administration of antidiarrheal medications led to symptom resolution, after which imatinib was successfully restarted at the same dose(108). In summary, this review suggests that imatinib could reduce RBC hemolysis in SCD, lessen the severity of pain crises, and improve patients’ responsiveness to analgesics by activating specific pathways. While these insights remain mostly hypothetical and sometimes conflicting, some benefits—such as lower hospitalization rates and shorter stays—have already been reported in SCD. However, the current evidence is still insufficient to support repurposing imatinib for SCD, and more studies are needed to confirm its clinical value. References 1. Pinto VM, Balocco M, Quintino S, Forni GL. Sickle cell disease: a review for the internist. 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Keywords no-donor properties of hydroxyurea sickle cell anemia sickle cell disease Authors Affiliations bijan keikhaei Ahvaz Jundishapur University of Medical Sciences Thalassemia and Hemoglobinopathy Research Center View all articles by this author Daryush Purrahman 0000-0002-8215-2686 Ahvaz Jundishapur University of Medical Sciences Thalassemia and Hemoglobinopathy Research Center View all articles by this author Najmeh Nameh Goshay Fard Ahvaz Jundishapur University of Medical Sciences Thalassemia and Hemoglobinopathy Research Center View all articles by this author Elham Abedi Shiraz University of Medical Science Department of Clinical Sciences View all articles by this author Farnoush Farokhian 0009-0001-8108-9259 Shiraz University of Medical Science Department of Clinical Sciences View all articles by this author Reyhane Khademi [email protected] Ahvaz Jundishapur University of Medical Sciences Thalassemia and Hemoglobinopathy Research Center View all articles by this author Metrics & Citations Metrics Article Usage 425 views 196 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation bijan keikhaei, Daryush Purrahman, Najmeh Nameh Goshay Fard, et al. 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