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Pediatric Hematology and Oncology 2023Children with acute lymphoblastic leukemia (ALL) are at high risk of developing long-term cardiometabolic complications during their survivorship. Maximal fat oxidation...
Children with acute lymphoblastic leukemia (ALL) are at high risk of developing long-term cardiometabolic complications during their survivorship. Maximal fat oxidation (MFO) is a marker during exercise of cardiometabolic health, and is associated with metabolic risk factors. Our aim was to characterize the carbohydrate and fat oxidation during exercise in childhood ALL survivors. Indirect calorimetry was measured in 250 childhood ALL survivors to quantify substrate oxidation rates during a cardiopulmonary exercise test. A best-fit third-order polynomial curve was computed for fat oxidation rate (mg/min) against exercise intensity (%Opeak) and was used to determine the MFO and the peak fat oxidation (Fat). The crossover point was also identified. Differences between prognostic risk groups were assessed (ie, standard risk [SR], high risk with and without cardio-protective agent dexrazoxane [HR + DEX and HR]). MFO, Fat and crossover point were not different between the groups ( = .078; = .765; = .726). Fat and crossover point were achieved at low exercise intensities. A higher MFO was achieved by men in the SR group (287.8 ± 111.2 mg/min) compared to those in HR + DEX (239.8 ± 97.0 mg/min) and HR groups (229.3 ± 98.9 mg/min) ( = .04). Childhood ALL survivors have low fat oxidation during exercise and oxidize carbohydrates at low exercise intensities, independently of the cumulative doses of doxorubicin they received. These findings alert clinicians on the long-term impact of cancer treatments on childhood ALL survivors' substrate oxidation.
Topics: Male; Child; Humans; Adipose Tissue; Oxygen Consumption; Oxidation-Reduction; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survivors; Cardiovascular Diseases
PubMed: 37440691
DOI: 10.1080/08880018.2023.2232399 -
Molecular and Cellular Biochemistry Aug 2021While anthracyclines (ACs) are a class of chemotherapeutic agents that have improved the prognosis of many women with breast cancer, it is one of the most cardiotoxic... (Review)
Review
While anthracyclines (ACs) are a class of chemotherapeutic agents that have improved the prognosis of many women with breast cancer, it is one of the most cardiotoxic agents used to treat cancer. Despite their reported dose-dependent cardiotoxicity, AC-based chemotherapy has become the mainstay of breast cancer therapy due to its efficacy. Elucidating the mechanisms of anthracycline-mediated cardiotoxicity and associated therapeutic interventions continue to be the main focus in the field of cardio-oncology. Herein, we summarized the current literature surrounding the mechanisms of anthracycline-induced cardiotoxicity, including the role of topoisomerase II inhibition, generation of reactive oxygen species, and elevations in free radicals. Furthermore, this review highlights the molecular mechanisms of potential cardioprotective interventions in this setting. The benefits of pharmaceuticals, including dexrazoxane, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, statins, and antioxidants in this setting, are reviewed. Finally, the mechanisms of emerging preventative interventions within this patient population including nutraceuticals and aerobic exercise are explored.
Topics: Animals; Anthracyclines; Breast Neoplasms; Cardiotonic Agents; Cardiotoxicity; Cardiotoxins; Female; Humans; Prognosis; Risk Factors
PubMed: 33835331
DOI: 10.1007/s11010-021-04152-y -
The Puzzle of Aspirin and Iron Deficiency: The Vital Missing Link of the Iron-Chelating Metabolites.International Journal of Molecular... May 2024Acetylsalicylic acid or aspirin is the most commonly used drug in the world and is taken daily by millions of people. There is increasing evidence that chronic... (Review)
Review
Acetylsalicylic acid or aspirin is the most commonly used drug in the world and is taken daily by millions of people. There is increasing evidence that chronic administration of low-dose aspirin of about 75-100 mg/day can cause iron deficiency anaemia (IDA) in the absence of major gastric bleeding; this is found in a large number of about 20% otherwise healthy elderly (>65 years) individuals. The mechanisms of the cause of IDA in this category of individuals are still largely unknown. Evidence is presented suggesting that a likely cause of IDA in this category of aspirin users is the chelation activity and increased excretion of iron caused by aspirin chelating metabolites (ACMs). It is estimated that 90% of oral aspirin is metabolized into about 70% of the ACMs salicyluric acid, salicylic acid, 2,5-dihydroxybenzoic acid, and 2,3-dihydroxybenzoic acid. All ACMs have a high affinity for binding iron and ability to mobilize iron from different iron pools, causing an overall net increase in iron excretion and altering iron balance. Interestingly, 2,3-dihydroxybenzoic acid has been previously tested in iron-loaded thalassaemia patients, leading to substantial increases in iron excretion. The daily administration of low-dose aspirin for long-term periods is likely to enhance the overall iron excretion in small increments each time due to the combined iron mobilization effect of the ACM. In particular, IDA is likely to occur mainly in populations such as elderly vegetarian adults with meals low in iron content. Furthermore, IDA may be exacerbated by the combinations of ACM with other dietary components, which can prevent iron absorption and enhance iron excretion. Overall, aspirin is acting as a chelating pro-drug similar to dexrazoxane, and the ACM as combination chelation therapy. Iron balance, pharmacological, and other studies on the interaction of iron and aspirin, as well as ACM, are likely to shed more light on the mechanism of IDA. Similar mechanisms of iron chelation through ACM may also be implicated in patient improvements observed in cancer, neurodegenerative, and other disease categories when treated long-term with daily aspirin. In particular, the role of aspirin and ACM in iron metabolism and free radical pathology includes ferroptosis, and may identify other missing links in the therapeutic effects of aspirin in many more diseases. It is suggested that aspirin is the first non-chelating drug described to cause IDA through its ACM metabolites. The therapeutic, pharmacological, toxicological and other implications of aspirin are incomplete without taking into consideration the iron binding and other effects of the ACM.
Topics: Humans; Aspirin; Anemia, Iron-Deficiency; Iron; Iron Chelating Agents; Salicylic Acid; Gentisates; Hippurates; Hydroxybenzoates
PubMed: 38791185
DOI: 10.3390/ijms25105150 -
International Journal of Molecular... Apr 2024The supply and control of iron is essential for all cells and vital for many physiological processes. All functions and activities of iron are expressed in conjunction... (Review)
Review
The supply and control of iron is essential for all cells and vital for many physiological processes. All functions and activities of iron are expressed in conjunction with iron-binding molecules. For example, natural chelators such as transferrin and chelator-iron complexes such as haem play major roles in iron metabolism and human physiology. Similarly, the mainstay treatments of the most common diseases of iron metabolism, namely iron deficiency anaemia and iron overload, involve many iron-chelator complexes and the iron-chelating drugs deferiprone (L1), deferoxamine (DF) and deferasirox. Endogenous chelators such as citric acid and glutathione and exogenous chelators such as ascorbic acid also play important roles in iron metabolism and iron homeostasis. Recent advances in the treatment of iron deficiency anaemia with effective iron complexes such as the ferric iron tri-maltol complex (feraccru or accrufer) and the effective treatment of transfusional iron overload using L1 and L1/DF combinations have decreased associated mortality and morbidity and also improved the quality of life of millions of patients. Many other chelating drugs such as ciclopirox, dexrazoxane and EDTA are used daily by millions of patients in other diseases. Similarly, many other drugs or their metabolites with iron-chelation capacity such as hydroxyurea, tetracyclines, anthracyclines and aspirin, as well as dietary molecules such as gallic acid, caffeic acid, quercetin, ellagic acid, maltol and many other phytochelators, are known to interact with iron and affect iron metabolism and related diseases. Different interactions are also observed in the presence of essential, xenobiotic, diagnostic and theranostic metal ions competing with iron. Clinical trials using L1 in Parkinson's, Alzheimer's and other neurodegenerative diseases, as well as HIV and other infections, cancer, diabetic nephropathy and anaemia of inflammation, highlight the importance of chelation therapy in many other clinical conditions. The proposed use of iron chelators for modulating ferroptosis signifies a new era in the design of new therapeutic chelation strategies in many other diseases. The introduction of artificial intelligence guidance for optimal chelation therapeutic outcomes in personalised medicine is expected to increase further the impact of chelation in medicine, as well as the survival and quality of life of millions of patients with iron metabolic disorders and also other diseases.
Topics: Humans; Iron Overload; Iron Chelating Agents; Anemia, Iron-Deficiency; Iron; Animals; Deferiprone
PubMed: 38731873
DOI: 10.3390/ijms25094654 -
Journal of Clinical Oncology : Official... Jul 2020To determine whether dexrazoxane provides effective cardioprotection during frontline treatment of pediatric acute myeloid leukemia (AML) without increasing relapse risk...
PURPOSE
To determine whether dexrazoxane provides effective cardioprotection during frontline treatment of pediatric acute myeloid leukemia (AML) without increasing relapse risk or noncardiac toxicities of the chemotherapy regimens.
PATIENTS AND METHODS
This was a multicenter study of all pediatric patients with AML without high allelic ratio FLT3/ITD treated in the Children's Oncology Group trial AAML1031 between 2011 and 2016. Median follow-up was 3.5 years. Dexrazoxane was administered at the discretion of treating physicians and documented at each course. Ejection fraction (EF) and shortening fraction (SF) were recorded after each course and at regular intervals in follow-up. Per protocol, anthracyclines were to be withheld if there was evidence of left ventricular systolic dysfunction (LVSD) defined as SF < 28% or EF < 55%. Occurrence of LVSD, trends in EF and SF, 5-year event-free survival (EFS) and overall survival (OS), and treatment-related mortality (TRM) were compared by dexrazoxane exposure.
RESULTS
A total of 1,014 patients were included in the analyses; 96 were exposed to dexrazoxane at every anthracycline course, and 918 were never exposed. Distributions of sex, age, race, presenting WBC count, risk group, treatment arm, and compliance with cardiac monitoring were similar for dexrazoxane-exposed and -unexposed patients. Dexrazoxane-exposed patients had significantly smaller EF and SF declines than unexposed patients across courses and a lower risk for LVSD (26.5% 42.2%; hazard ratio, 0.55; 95% CI, 0.36 to 0.86; = .009). Dexrazoxane-exposed patients had similar 5-year EFS (49.0% 45.1%; = .534) and OS (65.0% 61.9%; = .613) to those unexposed; however, there was a suggestion of lower TRM with dexrazoxane (5.7% 12.7%; = .068).
CONCLUSION
Dexrazoxane preserved cardiac function without compromising EFS and OS or increasing noncardiac toxicities. Dexrazoxane should be considered for cardioprotection during frontline treatment of pediatric AML.
Topics: Cardiotonic Agents; Child; Child, Preschool; Dexrazoxane; Female; Humans; Infant; Infant, Newborn; Leukemia, Myeloid, Acute; Male; Treatment Outcome; Ventricular Function, Left
PubMed: 32343641
DOI: 10.1200/JCO.19.02856 -
Translational Pediatrics May 2023Adamantinoma craniopharyngioma (ACP) is a non-malignant tumour of unknown pathogenesis that frequently occurs in children and has malignant potential. The main treatment...
BACKGROUND
Adamantinoma craniopharyngioma (ACP) is a non-malignant tumour of unknown pathogenesis that frequently occurs in children and has malignant potential. The main treatment options are currently surgical resection and radiotherapy. These treatments can lead to serious complications that greatly affect the overall survival and quality of life of patients. It is therefore important to use bioinformatics to explore the mechanisms of ACP development and progression and to identify new molecules.
METHODS
Sequencing data of ACP was downloaded from the comprehensive gene expression database for differentially expressed gene identification and visualized by Gene Ontology, Kyoto Gene, and gene set enrichment analyses (GSEAs). Weighted correlation network analysis was used to identify the genes most strongly associated with ACP. GSE94349 was used as the training set and five diagnostic markers were screened using machine learning algorithms to assess diagnostic accuracy using receiver operating characteristic (ROC) curves, while GSE68015 was used as the validation set for verification.
RESULTS
Type I cytoskeletal 15 (KRT15), Follicular dendritic cell secreted peptide (FDCSP), Rho-related GTP-binding protein RhoC (RHOC), Modulates negatively TGFB1 signaling in keratinocytes (CD109), and type II cytoskeletal 6A (KRT6A) (area under their receiver operating characteristic curves is 1 for both the training and validation sets), Nomograms constructed using these five markers can predict progression of ACP patients. Whereas ACP tissues with activated T-cell surface glycoprotein CD4, Gamma delta T cells, eosinophils and regulatory T cells were expressed at higher levels than in normal tissues, which may contribute to the pathogenesis of ACP. According to the analysis of the CellMiner database (Tumor cell and drug related database tools), high CD109 levels showed significant drug sensitivity to Dexrazoxane, which has the potential to be a therapeutic agent for ACP.
CONCLUSIONS
Our findings extend understandings of the molecular immune mechanisms of ACP and suggest possible biomarkers for the targeted and precise treatment of ACP.
PubMed: 37305719
DOI: 10.21037/tp-23-152 -
BioMed Research International 2022Doxorubicin (Dox) is an effective chemotherapeutic drug for the treatment of various cancers. Due to its potential fatal cardiotoxic side effects, the clinical... (Review)
Review
Doxorubicin (Dox) is an effective chemotherapeutic drug for the treatment of various cancers. Due to its potential fatal cardiotoxic side effects, the clinical application is often limited. Dexrazoxane (Dex) is the only drug approved by the Food and Drug Administration (FDA) for the prevention of Dox-induced cardiotoxicity but has side effects. Thus, more protective strategies should be explored. If NAD plays a role in maintaining heart function, its precursor prospectively alleviates Dox-induced cellular injury. Here, we studied the protective effects of nicotinic acid riboside (NAR) on Dox-induced cardiotoxicity and . We found that NAR significantly improved the cardiac function of Dox-treated mice by restoring ejection fraction (EF), fractional shortening (FS), and serum level of cardiac troponin (cTnI). NAR not only reduced malondialdehyde (MDA), lactate dehydrogenase (LDH), and reactive oxygen species (ROS) levels in Dox-treated cardiomyocytes but also further promoted the activities of cardiac superoxide dismutase (SOD) and glutathione (GSH). Following exposure to 5 M Dox, cotreatment with NAR exhibited increased cell viability with a decrease in the apoptosis cell population. Moreover, the levels of apoptosis-related proteins, as well as proteins involved in oxidative stress and autophagy, were altered after NAR treatment. Collectively, these findings underline the protective potential of NAR against Dox-induced cardiomyocyte injury by regulating Nrf-2/P62-related oxidative stress and autophagy, which could potentially promote survival.
Topics: Antineoplastic Agents; Apoptosis Regulatory Proteins; Cardiotonic Agents; Cardiotoxicity; Dexrazoxane; Doxorubicin; Humans; Niacinamide; Oxidative Stress; Pyridinium Compounds
PubMed: 35242876
DOI: 10.1155/2022/6293329 -
Biomedicine & Pharmacotherapy =... Aug 2021Cancer is one of the leading causes of deaths worldwide with 18.1 million deaths per year. Although there have been significant advances in anti-cancer therapies, they... (Comparative Study)
Comparative Study
Cancer is one of the leading causes of deaths worldwide with 18.1 million deaths per year. Although there have been significant advances in anti-cancer therapies, they can often result in side effects with cardiovascular complications being the most severe. Dexrazoxane is the only currently approved treatment for prevention of anthracycline induced cardiotoxicity but there are concerns about its use due to the development of secondary malignancies and myelodysplastic syndrome. Additionally, it is only recommended in patients who are due to receive a total cumulative dose of 300 mg/m of doxorubicin or 540 mg/m of epirubicin. Thus, there exists an urgent need to develop new therapeutic strategies to counteract anthracycline induced cardiotoxicity. The h9c2 cardiomyoblast was investigated for its differentiation capacity and used to screen and compare promising prophylactics for doxorubicin induced cardiotoxicity. The half maximal inhibitory concentration of doxorubicin was determined in differentiated h9c2 cells after 24 h of exposure, to establish a model for drug screening. Cells were treated with dexrazoxane, resveratrol, and carvedilol either 3 h or 24 h prior to doxorubicin treatment. The ability of these cardioprotectants to prevent cardiotoxicity was analysed using the cck-8 cell viability assay and the dichlorofluorescin diacetate (DCFDA) reactive oxygen species (ROS) assay. There was no significant increase in survival in treatment groups after 3 h, however, at 24 h, resveratrol significantly improved survival compared to all other groups (p < 0.05). Additionally, dexrazoxane and resveratrol significantly decreased ROS formation at 3 h (p < 0.05) and all groups significantly decreased ROS production at 24 h (p < 0.001). This work is the first comparison of these cardioprotectants and suggests that resveratrol may be a more effective treatment in the prevention of anthracycline induced cardiotoxicity, compared to dexrazoxane and carvedilol. However, further work will be needed in order to decipher the exact mechanism and potential of this drug in the clinic.
Topics: Animals; Antibiotics, Antineoplastic; Cardiotonic Agents; Cardiotoxicity; Carvedilol; Cell Line; Cell Survival; Dexrazoxane; Doxorubicin; Rats; Reactive Oxygen Species; Resveratrol
PubMed: 34015579
DOI: 10.1016/j.biopha.2021.111702 -
Mutation Research. Genetic Toxicology... Jan 2020Bioflavonoids have a similar chemical structure to etoposide, the well-characterized topoisomerase II (Top2) poison, and evidence shows that they also induce DNA...
Bioflavonoids have a similar chemical structure to etoposide, the well-characterized topoisomerase II (Top2) poison, and evidence shows that they also induce DNA double-strand breaks (DSBs) and promote genome rearrangements. The purpose of this study was to determine the kinetics of bioflavonoid-induced DSB appearance and repair, and their dependence on Top2. Cells were exposed to bioflavonoids individually or in combination in the presence or absence of the Top2 catalytic inhibitor dexrazoxane. The kinetics of appearance and repair of γH2AX foci were measured. In addition, the frequency of resultant MLL-AF9 breakpoint cluster region translocations was determined. Bioflavonoids readily induced the appearance of γH2AX foci, but bioflavonoid combinations did not act additively or synergistically to promote DSBs. Myricetin-induced DSBs were mostly reduced by dexrazoxane, while genistein and quercetin-induced DSBs were only partially, but significantly, reduced. By contrast, luteolin and kaempferol-induced DSBs increased with dexrazoxane pre-treatment. Sensitivity to Top2 inhibition correlated with a significant reduction of bioflavonoid-induced MLL-AF9 translocations. These data demonstrate that myricetin, genistein, and quercetin act most similar to etoposide although with varying Top2-dependence. By contrast, luteolin and kaempferol have distinct kinetics that are mostly Top2-independent. These findings have implications for understanding the mechanisms of bioflavonoid activity and the potential of individual bioflavonoids to promote chromosomal translocations. Further, they provide direct evidence that specific Top2 inhibitors or targeted drugs could be developed that possess less leukemic potential or suppress chromosomal translocations associated with therapy-related and infant leukemias.
Topics: Animals; Cell Line; Chromosome Breakpoints; Chromosomes, Mammalian; DNA; DNA Breaks, Double-Stranded; DNA Repair; DNA Topoisomerases, Type II; Dexrazoxane; Etoposide; Flavonoids; Genistein; Histones; Kaempferols; Luteolin; Mice; Mouse Embryonic Stem Cells; Quercetin; Topoisomerase II Inhibitors; Translocation, Genetic
PubMed: 32087851
DOI: 10.1016/j.mrgentox.2020.503144 -
Cardio-oncology (London, England) Jun 2021Cancer therapy-related cardiac dysfunction may occur in pediatric cancer survivors. Identification of early markers of myocardial damage secondary to anthracycline...
BACKGROUND
Cancer therapy-related cardiac dysfunction may occur in pediatric cancer survivors. Identification of early markers of myocardial damage secondary to anthracycline exposure is crucial to develop strategies that may ameliorate this complication.
OBJECTIVES
The purpose of this study was to identify early myocardial changes induced by doxorubicin with and without cardioprotection using dexrazoxane detected by serial cardiac magnetic resonance imaging (CMR) in a pre-clinical mouse model.
METHODS
Serial CMR examinations were performed in 90 mice distributed in 3 groups: 45 received doxorubicin (DOX group), 30 mice received doxorubicin with dexrazoxane (DOX/DEX group) and 15 mice received saline injections (control group). We obtained the following CMR parameters in all mice: T2, extracellular volume quantification (ECV), myocardial deformation, and functional quantification.
RESULTS
Myocardial edema assessed by T2 time was the earliest parameter demonstrating evidence of myocardial injury, most notable in the DOX group at week 4 and 8 compared with DOX/DEX group. Similarly, global longitudinal strain was abnormal in both the DOX and DOX/DEX groups. However, this change persisted only in the DOX group. The ECV was significantly elevated in the DOX group at the final CMR, while only minimally elevated in the DOX/DEX group. The right and left ejection fraction was decreased, along with the mass to volume ratio in the DOX group. The T2 time, ECV, and deformation correlated with ejection fraction and left ventricular volume.
CONCLUSIONS
T2 time and deformation by CMR identifies early myocardial injury from anthracyclines. Dexrazoxne did not prevent the initial edema, but the inflammatory changes were not sustained. CMR may be useful for early detection of cardiac dysfunction. Serial CMR demonstrates dexrazoxane minimizes cardiac dysfunction and aids recovery in a mouse model.
PubMed: 34134789
DOI: 10.1186/s40959-021-00109-8