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Antioxidants (Basel, Switzerland) Mar 2024Acute lymphoblastic leukaemia (ALL) is the most prevalent cancer in children, and excessive iron buildup resulting from blood transfusions and chemotherapy potentially...
Acute lymphoblastic leukaemia (ALL) is the most prevalent cancer in children, and excessive iron buildup resulting from blood transfusions and chemotherapy potentially has a negative impact on treatment outcomes and prognosis in patients with ALL. Therefore, initiating early iron chelation therapy during ALL treatment is a logical approach. Ideally, the selected iron chelator should also possess anti-leukaemia properties. The aim of the present study was to explore the potential impact and underlying mechanism of deferasirox (DFX) in ALL therapy. This study proved that DFX, an iron chelator, is capable of inducing leukaemia cell death through ferroptosis, which is achievable by increasing the expression of acetylated nuclear factor erythroid 2-related factor 2 (NRF2). More specifically, NRF2 acetylation on Lys599 was facilitated by acetyltransferase-p300/CBP. These findings indicate that DFX could serve as a potent adjunctive medication for patients with ALL. Moreover, DFX may offer dual benefits in ALL treatment, functioning as both an iron chelator and NRF2-modulating agent. Further research and clinical trials are necessary to fully elucidate the therapeutic potential of DFX in patients with ALL and incorporate it into treatment protocols.
PubMed: 38671872
DOI: 10.3390/antiox13040424 -
Heliyon Oct 2020Iron is an essential trace metal for all biological processes and plays a role in almost every aspect of body growth. Previously, we found that iron-depletion...
Iron is an essential trace metal for all biological processes and plays a role in almost every aspect of body growth. Previously, we found that iron-depletion downregulated the expression of proteins, arginine methyltransferase-1 and 3 (PRMT1 and PRMT3), by an iron-specific chelator, deferoxamine (DFO), in rat liver FAO cell line using DNA microarray analysis (unpublished data). However, regulatory mechanisms underlying the association between iron deficiency and PRMT expression are unclear and . In the present study, we revealed that the treatment of cells with two iron-specific chelators, DFO and deferasirox (DFX), downregulated the gene and protein expression of PRMT1 and 3 as compared with the untreated cells. Subsequently, DFO and DFX treatments decreased protein methylation. Importantly, these effects were attenuated by a holo-transferrin treatment. Furthermore, weanling Wistar-strain rats were fed a control diet or an iron-deficient diet for 4 weeks. Dietary iron deficiency was found to decrease the concentration of hemoglobin and liver iron while increasing the heart weight. PRMT and protein methylation levels were also significantly reduced in the iron-deficient group as compared to the control group. To our knowledge, this is the first study to demonstrate that PRMT levels and protein methylation are reduced in iron-deficient models, and .
PubMed: 33033759
DOI: 10.1016/j.heliyon.2020.e05059 -
Expert Review of Hematology Feb 2023Regular blood transfusions in patients with thalassemia syndromes can cause iron overload resulting in complications including cirrhosis, heart problems, or endocrine...
INTRODUCTION
Regular blood transfusions in patients with thalassemia syndromes can cause iron overload resulting in complications including cirrhosis, heart problems, or endocrine abnormalities. To prevent iron overload toxicity in these patients, three iron chelators are currently FDA-approved for use: deferoxamine, deferasirox, and deferiprone. In the United States, deferiprone has been approved for three times daily dosing since 2011 and has recently gained approval for twice-daily administration.
AREAS COVERED
A PubMed literature search was performed with the keywords 'deferiprone' and 'thalassemia.' Relevant original research studying deferiprone's effects on transfusional iron overload in patients with thalassemia syndromes was included. Exclusion criteria included case reports and review papers. Deferiprone is effective at reducing serum ferritin levels in patients with iron overload. Twice-daily administration provides a similar level of iron chelation as three times daily dosing with a comparable side effect profile and increased patient acceptability.
EXPERT OPINION
New studies are highlighting deferiprone's potential for combination therapy with either deferoxamine or deferasirox to improve iron chelation. Deferiprone's ability to significantly decrease cardiac and liver iron content can be utilized in other transfusion-dependent hematologic conditions, as evidenced by its recent approval for use in the United States for sickle cell disease or other anemias.
Topics: Humans; Deferasirox; Deferoxamine; Syndrome; Iron Overload; Iron Chelating Agents; Thalassemia; Blood Transfusion; Pyridones; Benzoates
PubMed: 36755516
DOI: 10.1080/17474086.2023.2178409 -
Cancer Medicine May 2020Drug resistance is a fundamental clinical concern in pediatric acute lymphoblastic leukemia (pALL), and methotrexate (MTX) is an essential chemotherapy drug administered...
Drug resistance is a fundamental clinical concern in pediatric acute lymphoblastic leukemia (pALL), and methotrexate (MTX) is an essential chemotherapy drug administered for the treatment. In the current study, the effect of iron in response to methotrexate and its underlying mechanisms were investigated in pALL cells. CCRF-CEM and Nalm6 cell lines were selected as T and B-ALL subtypes. Cells were pretreated with ferric ammonium citrate, exposed to the IC50 concentration of MTX and cell viability was assessed using MTT, colony formation, and flow cytometry assays. Iron-loaded cells were strongly resistant to MTX cytotoxicity. The inhibitory effect of N-acetyl cysteine to reverse the acquired MTX resistance was greater than that of the iron chelator, deferasirox, highlighting the importance of iron-mediated ROS in MTX resistance. Subsequently, the upregulation of BCL2, SOD2, NRF2, and MRP1 was confirmed using quantitative RT-PCR. Moreover, a positive correlation was demonstrated between the MRP1 expression levels and bone marrow iron storage in pALL patients. Further supporting our findings were the hematoxylin and eosin-stained histological sections showing that iron-treated nude mice xenografts demonstrated significantly more liver damage than those unexposed to iron. Overall, iron is introduced as a player with a novel role contributing to methotrexate resistance in pALL. Our findings suggest that the patients' bone marrow iron stores are necessary to be assessed during the chemotherapy, and transfusions should be carefully administrated.
Topics: Acetylcysteine; Bone Marrow; Cell Line, Tumor; Cell Survival; Child; Child, Preschool; Deferasirox; Drug Resistance, Neoplasm; Female; Ferric Compounds; Free Radical Scavengers; Humans; Infant; Inhibitory Concentration 50; Iron; Iron Chelating Agents; Male; Methotrexate; Multidrug Resistance-Associated Proteins; NF-E2-Related Factor 2; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins c-bcl-2; Quaternary Ammonium Compounds; RNA, Messenger; Reactive Oxygen Species; Superoxide Dismutase; Transcriptome; Up-Regulation
PubMed: 32176452
DOI: 10.1002/cam4.2982 -
Biology Feb 2022Thalassemic syndromes are characterized by clinical heterogenicity. For severe disease forms, lifelong blood transfusions remain the mainstay of therapy, while iron...
Thalassemic syndromes are characterized by clinical heterogenicity. For severe disease forms, lifelong blood transfusions remain the mainstay of therapy, while iron overload monitoring and adequate chelation treatment are required in order to ensure effective disease management. Compared to previous chelators, the new deferasirox film-coated tablet (DFX FCT) is considered to offer a more convenient and well-tolerated treatment scheme, aiming at better treatment-related and patient-related outcomes. The present study's objective was to prospectively evaluate the safety and efficacy of DFX FCT in children and adolescents with transfusion-dependent thalassemia. Data collected included patient demographics, hematology and biochemistry laboratory work up, magnetic resonance imaging of heart and liver for iron load, as well as ophthalmological and audiological examination prior to and a year following drug administration. Study results confirmed DFX FCT safety in older children in a manner similar to adults, but demonstrated increased frequency of adverse events in younger patients, mainly, involving liver function. With regards to efficacy, study results confirmed the preventive role of DFX FCT in iron loading of liver and heart, however, higher doses than generally recommended were required in order to ensure adequate chelation.
PubMed: 35205113
DOI: 10.3390/biology11020247 -
BMC Nephrology Dec 2021Renal injury in transfusion dependent β thalassemia patients (TDT) has been attributed to iron overload, chronic anemia and iron-chelation therapy (ICT) toxicity. We... (Comparative Study)
Comparative Study
BACKGROUND
Renal injury in transfusion dependent β thalassemia patients (TDT) has been attributed to iron overload, chronic anemia and iron-chelation therapy (ICT) toxicity. We studied renal function in TDT patients treated with two different ICT regimes.
PATIENTS AND METHODS
We studied 36 TDT patients: 26 received deferasirox (DFX) and 10 were treated with deferoxamine (DFO) +/- deferiprone (DFP).
RESULTS
Increased uNAG was found in 30% of the DFX group vs. 10% of the DFO+/-DFP group, the mean uNAG level in the DFX group was significantly higher than in the DFO+/-DFP group, (P < 0.05). A moderate negative correlation was found between uNAG levels and mean serum ferritin for the prior 10 years (P = 0.03), more pronounced for the DFO+/-DFP group. Twenty nine patients had had their renal function evaluated 10 years earlier; eGFR significantly declined in patients switched to DFX (P = 0.0093) but not in patients who continued DFO+/-DFP.
CONCLUSIONS
A high prevalence of renal tubular damage was observed in our TDT patients, particularly those treated with DFX; uNAG was negatively associated with mean 10-year serum ferritin, suggesting ICT's involvement in tubular injury. A significant decline in eGFR compared to a decade earlier was observed only in patients currently treated with DFX. Strict follow-up of renal function in TDT patients is warranted.
Topics: Adolescent; Adult; Child; Child, Preschool; Deferasirox; Deferoxamine; Female; Humans; Iron Chelating Agents; Kidney; Male; Middle Aged; Retrospective Studies; Young Adult; beta-Thalassemia
PubMed: 34930156
DOI: 10.1186/s12882-021-02630-5 -
Antimicrobial Agents and Chemotherapy Sep 2019is a biofilm-forming opportunistic pathogen and is intrinsically resistant to many antibiotics. In a high-throughput screen for molecules that modulate biofilm...
is a biofilm-forming opportunistic pathogen and is intrinsically resistant to many antibiotics. In a high-throughput screen for molecules that modulate biofilm formation, we discovered that the thiopeptide antibiotic thiostrepton (TS), which is considered to be inactive against Gram-negative bacteria, stimulated biofilm formation in a dose-dependent manner. This phenotype is characteristic of exposure to antimicrobial compounds at subinhibitory concentrations, suggesting that TS was active against Supporting this observation, TS inhibited the growth of a panel of 96 multidrug-resistant (MDR) clinical isolates at low-micromolar concentrations. TS also had activity against clinical isolates. The expression of Tsr, a 23S rRNA-modifying methyltransferase from TS producer , in conferred TS resistance, confirming that the drug acted via its canonical mode of action, inhibition of ribosome function. The deletion of oligopeptide permease systems used by other peptide antibiotics for uptake failed to confer TS resistance. TS susceptibility was inversely proportional to iron availability, suggesting that TS exploits uptake pathways whose expression is increased under iron starvation. Consistent with this finding, TS activity against and was potentiated by the FDA-approved iron chelators deferiprone and deferasirox and by heat-inactivated serum. Screening of mutants for TS resistance revealed that it exploits pyoverdine receptors FpvA and FpvB to cross the outer membrane. We show that the biofilm stimulation phenotype can reveal cryptic subinhibitory antibiotic activity, and that TS has activity against select multidrug-resistant Gram-negative pathogens under iron-limited growth conditions, similar to those encountered at sites of infection.
Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Bacterial Outer Membrane Proteins; Bacterial Proteins; Biofilms; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Iron Chelating Agents; Membrane Proteins; Microbial Sensitivity Tests; Mutation; Pseudomonas aeruginosa; Thiostrepton
PubMed: 31262758
DOI: 10.1128/AAC.00472-19 -
Orphanet Journal of Rare Diseases Apr 2021Transfusion-dependent thalassaemia (TDT) is a hereditary blood disorder in which blood transfusion is the mainstay treatment to prolong survival and improve quality of...
BACKGROUND
Transfusion-dependent thalassaemia (TDT) is a hereditary blood disorder in which blood transfusion is the mainstay treatment to prolong survival and improve quality of life. Patients with this disease require blood transfusion at more than 100 ml/kg annually and iron-chelating therapy (ICT) to prevent iron overload (IOL) complications. There are substantial numbers of TDT patients in Malaysia, but limited data are available regarding the economic burden associated with this disease. The purpose of this study was to determine the lifetime cost of TDT from a societal perspective and identify potential factors increasing patient and family expenditures among thalassaemia populations.
METHODS
The total lifetime cost per TDT patient (TC1) is the sum of lifetime healthcare cost (TC2) and lifetime patient and family healthcare expenditure (TC3). TC2 was simulated using the Markov model, taking into account all costs subsidized by the government, and TC3 was estimated through a cross-sectional health survey approach. A survey was performed using a two-stage sampling method in 13 thalassaemia centres covering all regions in Malaysia.
RESULTS
A TDT patient is expected to incur TC2 of USD 561,208. ICT was the main driver of cost and accounted for 56.9% of the total cost followed by blood transfusion cost at 13.1%. TC3 was estimated to be USD 45,458. Therefore, the estimated TC1 of a TDT patient was USD 606,665. Sensitivity analyses showed that if all patients were prescribed oral ICT deferasirox for their lifetime, the total healthcare cost would increase by approximately 65%. Frequency of visits to health facilities for blood transfusion/routine monitoring and patients who were prescribed desferrioxamine were observed to be factors affecting patient and family monthly expenses.
CONCLUSION
The lifetime cost per TDT patient was USD 606,665, and this result may be useful for national health allocation planning. An estimation of the economic burden will provide additional information to decision makers on implementing prevention interventions to reduce the number of new births and medical service reimbursement.
Topics: Benzoates; Blood Transfusion; Cost of Illness; Cross-Sectional Studies; Deferasirox; Deferoxamine; Humans; Malaysia; Quality of Life; Thalassemia; Triazoles
PubMed: 33827621
DOI: 10.1186/s13023-021-01791-8 -
Frontiers in Medicine 2021Management of β-thalassemia in developing countries is demanding in the absence of available therapies rather than recurrent transfusions. This study describes the...
Management of β-thalassemia in developing countries is demanding in the absence of available therapies rather than recurrent transfusions. This study describes the characteristics and evaluates the hematological, biochemical, and hormonal findings of patients with β-thalassemia in the West Bank. We conducted a retrospective cohort study between January 2017 and December 2018. Data were collected through medical files of the patients with β-thalassemia from eight primary healthcare clinics, nine emergency departments, and 11 governmental hospitals across the West Bank. Results of the hematological, biochemical, and hormonal evaluations, in addition to demographic data and the use of iron chelation were included in the study and analyzed. A total of 309 patients with β-thalassemia were included with a male-to-female ratio of 1:1 and an average age of 23.4 ± 10.4 years. The anemic presentation was reported in 78.6% of the patients as indicated by hemoglobin level (mean ± SD = 8.4 ± 1.4 g/dl), and 73.1% had iron overload with serum ferritin (SF) levels ≥ 1,000 μg/L (mean ± SD = 317.8 ± 3,378.8 μg/L). Evaluation of the liver function tests showed that alanine transaminase (ALT) and aspartate transaminase (AST) levels were high among 38.1 and 61.2% of the patients, respectively. ALT and AST showed significant positive correlations with SF levels, while the kidney tests did not. As for iron chelation medications, patients receiving deferoxamine (26.5%) showed significantly higher SF levels compared with patients receiving deferasirox (73.5%). This study highlights the importance of establishing patient-tailored comprehensive assessment and follow-up protocols for the management of β-thalassemia with an emphasis on blood transfusion and iron chelation practices.
PubMed: 34988098
DOI: 10.3389/fmed.2021.788758