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JACC. CardioOncology Apr 2024
PubMed: 38774009
DOI: 10.1016/j.jaccao.2024.01.004 -
Cureus Jun 2021Multiple myeloma is a pathology of plasma cells, with one of the most common side effects of its treatment is heart failure. In addition, cardiac amyloidosis could cause... (Review)
Review
Multiple myeloma is a pathology of plasma cells, with one of the most common side effects of its treatment is heart failure. In addition, cardiac amyloidosis could cause heart failure by itself. Even though mechanisms of cardiac amyloidosis are known, and they involve lysosomal dysfunction, reactive oxygen species (ROS) accumulation, and infiltrative effect by fibrils, there is no specific agent that could protect from these effects. While the molecular mechanism of doxorubicin cardiotoxicity via topoisomerase II β is established, the only FDA-approved agent for treatment is dexrazoxane. Liposomal doxorubicin can potentially improve response and decrease the development of heart failure due to microscopic liposomes that can accumulate and penetrate only tumor vasculature. Supplements that enhance mitochondrial biogenesis are also shown to improve doxorubicin-induced cardiotoxicity. Other agents, such as JR-311, ICRF-193, and ursolic acid, could potentially become new treatment options. Proteasome inhibitors, novel agents, have significantly improved survival rates among multiple myeloma patients. They act on a proteasome system that is highly active in cardiomyocytes and activates various molecular cascades in malignant cells, as well as in the heart, through nuclear factor kappa B (NF-kB), endoplasmic reticulum (ER), calcineurin-nuclear factor of activated T-cells (NFAT), and adenosine monophosphate-activated protein kinase (AMPKa)/autophagy pathways. Metformin, apremilast, and rutin have shown positive results in animal studies and may become a promising therapy as cardioprotective agents. This article aims to highlight the main molecular mechanisms of heart failure among patients with multiple myeloma and potential treatment options to facilitate the development and research of new preventive strategies. Hence, this will have a positive impact on life expectancy in patients with multiple myeloma.
PubMed: 34336442
DOI: 10.7759/cureus.15943 -
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 -
JACC. CardioOncology Sep 2019The authors performed a systematic review and meta-analysis of randomized and nonrandomized trials on the efficacy of dexrazoxane in patients with breast cancer who were...
OBJECTIVES
The authors performed a systematic review and meta-analysis of randomized and nonrandomized trials on the efficacy of dexrazoxane in patients with breast cancer who were treated with anthracyclines with or without trastuzumab.
BACKGROUND
Breast cancer treatment with anthracyclines and trastuzumab is associated with an increased risk of cardiotoxicity. Among the various strategies to reduce the risk of cardiotoxicity, dexrazoxane is an option for primary prevention, but it is seldom used in clinical practice.
METHODS
Online databases were searched from January 1990 up to March 1, 2019, for clinical trials on the use of dexrazoxane for the prevention of cardiotoxicity in patients with breast cancer receiving anthracyclines with or without trastuzumab. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects model meta-analysis.
RESULTS
Seven randomized trials and 2 retrospective trials with a total of 2,177 patients were included. Dexrazoxane reduced the risk of clinical heart failure (RR: 0.19; 95% CI: 0.09 to 0.40; p < 0.001) and cardiac events (RR: 0.36; 95% CI: 0.27 to 0.49; p < 0.001) irrespective of previous exposure to anthracyclines. The rate of a partial or complete oncological response, overall survival, and progression-free survival were not affected by dexrazoxane.
CONCLUSIONS
Dexrazoxane reduced the risk of clinical heart failure and cardiac events in patients with breast cancer undergoing anthracycline chemotherapy with or without trastuzumab and did not significantly impact cancer outcomes. However, the quality of available evidence is low, and further randomized trials are warranted before the systematic implementation of this therapy in clinical practice.
PubMed: 34396164
DOI: 10.1016/j.jaccao.2019.08.003 -
BioMed Research International 2020The usage of doxorubicin is hampered by its life-threatening cardiotoxicity in clinical practice. Dexrazoxane is the only cardioprotective medicine approved by the FDA...
The usage of doxorubicin is hampered by its life-threatening cardiotoxicity in clinical practice. Dexrazoxane is the only cardioprotective medicine approved by the FDA for preventing doxorubicin-induced cardiac toxicity. Nevertheless, the mechanism of dexrazoxane is incompletely understood. The aim of our study is to investigate the possible molecular mechanism of dexrazoxane against doxorubicin-induced cardiotoxicity. We established a doxorubicin-induced mouse and cardiomyocyte injury model. Male C57BL/6J mice were randomly distributed into a control group (Con), a doxorubicin treatment group (DOX), a doxorubicin plus dexrazoxane treatment group (DOX+DEX), and a dexrazoxane treatment group (DEX). Echocardiography and histology analyses were performed to evaluate heart function and structure. DNA laddering, qRT-PCR, and Western blot were performed on DOX-treated cardiomyocytes with/without DEX treatment in vitro. Cardiomyocytes were then transfected with miR-17-5p mimics or inhibitors in order to analyze its downstream target. Our results demonstrated that dexrazoxane has a potent effect on preventing cardiac injury induced by doxorubicin in vivo and in vitro by reducing cardiomyocyte apoptosis. MicroRNA plays an important role in cardiovascular diseases. Our data revealed that dexrazoxane could upregulate the expression of miR-17-5p, which plays a cytoprotective role in response to hypoxia by regulating cell apoptosis. Furthermore, the miRNA and protein analysis revealed that miR-17-5p significantly attenuated phosphatase and tensin homolog (PTEN) expression in cardiomyocytes exposed to doxorubicin. Taken together, dexrazoxane might exert a cardioprotective effect against doxorubicin-induced cardiomyocyte apoptosis by regulating the expression of miR-17-5p/PTEN cascade.
Topics: Animals; Apoptosis; Cardiotoxicity; Cell Survival; Dexrazoxane; Disease Models, Animal; Doxorubicin; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Myocytes, Cardiac; PTEN Phosphohydrolase; Protective Agents; Up-Regulation
PubMed: 32190669
DOI: 10.1155/2020/5107193 -
JACC. CardioOncology Apr 2024Older patients with Hodgkin lymphoma (HL) often have comorbid cardiovascular disease; however, the impact of pre-existing heart failure (HF) on the management and...
BACKGROUND
Older patients with Hodgkin lymphoma (HL) often have comorbid cardiovascular disease; however, the impact of pre-existing heart failure (HF) on the management and outcomes of HL is unknown.
OBJECTIVES
The aim of this study was to assess the prevalence of pre-existing HF in older patients with HL and its impact on treatment and outcomes.
METHODS
Linked Surveillance, Epidemiology, and End Results (SEER) and Medicare data from 1999 to 2016 were used to identify patients 65 years and older with newly diagnosed HL. Pre-existing HF, comorbidities, and cancer treatment were ascertained from billing codes and cause-specific mortality from SEER. The associations between pre-existing HF and cancer treatment were estimated using multivariable logistic regression. Cause-specific Cox proportional hazards models adjusted for comorbidities and cancer treatment were used to estimate the association between pre-existing HF and cause-specific mortality.
RESULTS
Among 3,348 patients (mean age 76 ± 7 years, 48.6% women) with newly diagnosed HL, pre-existing HF was present in 437 (13.1%). Pre-existing HF was associated with a lower likelihood of using anthracycline-based chemotherapy regimens (OR: 0.42; 95% CI: 0.29-0.60) and a higher likelihood of lymphoma mortality (HR: 1.25; 95% CI: 1.06-1.46) and cardiovascular mortality (HR: 2.57; 95% CI: 1.96-3.36) in models adjusted for comorbidities. One-year lymphoma mortality cumulative incidence was 37.4% (95% CI: 35.5%-39.5%) with pre-existing HF and 26.3% (95% CI: 25.0%-27.6%) without pre-existing HF. The cardioprotective medications dexrazoxane and liposomal doxorubicin were used in only 4.2% of patients.
CONCLUSIONS
Pre-existing HF in older patients with newly diagnosed HL is common and associated with higher 1-year mortality. Strategies are needed to improve lymphoma and cardiovascular outcomes in this high-risk population.
PubMed: 38774008
DOI: 10.1016/j.jaccao.2024.02.003 -
Journal of Enzyme Inhibition and... Dec 2020The significant role of topoisomerases in the control of DNA chain topology has been confirmed in numerous research conducted worldwide. The prevalence of these enzymes,... (Review)
Review
The significant role of topoisomerases in the control of DNA chain topology has been confirmed in numerous research conducted worldwide. The prevalence of these enzymes, as well as the key importance of topoisomerase in the proper functioning of cells, have made them the target of many scientific studies conducted all over the world. This article is a comprehensive review of knowledge about topoisomerases and their inhibitors collected over the years. Studies on the structure-activity relationship and molecular docking are one of the key elements driving drug development. In addition to information on molecular targets, this article contains details on the structure-activity relationship of described classes of compounds. Moreover, the work also includes details about the structure of the compounds that drive the mode of action of topoisomerase inhibitors. Finally, selected topoisomerases inhibitors at the stage of clinical trials and their potential application in the chemotherapy of various cancers are described.
Topics: Acridines; Animals; Antineoplastic Agents; DNA Topoisomerases; Dexrazoxane; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Quinolones; Structure-Activity Relationship; Thiobarbiturates; Topoisomerase Inhibitors
PubMed: 32975138
DOI: 10.1080/14756366.2020.1821676 -
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 -
Frontiers in Pharmacology 2023Dexrazoxane (DEX) is the only drug clinically approved to treat Doxorubicin-induced cardiotoxicity (DIC), however its impact on the anticancer efficacy of DOX is not...
Dexrazoxane (DEX) is the only drug clinically approved to treat Doxorubicin-induced cardiotoxicity (DIC), however its impact on the anticancer efficacy of DOX is not extensively studied. In this manuscript, a proof-of-concept study is carried out to quantitatively characterize the anticancer effects of DOX and DEX and determine their nature of drug-drug interactions in cancer cells by combining experimental data with modeling approaches. First, we determined the static concentration-response of DOX and DEX in breast cancer cell lines, JIMT-1 and MDA-MB-468. With a three-dimensional (3D) response surface analysis using a competitive interaction model, we characterized their interaction to be modestly synergistic in MDA-MB-468 or modestly antagonistic in JIMT-1 cells. Second, a cellular-level, pharmacodynamic (PD) model was developed to capture the time-course effects of the two drugs which determined additive and antagonistic interactions for DOX and DEX in MDA-MB-468 and JIMT-1, respectively. Finally, we performed to translation by utilizing DOX and DEX clinical dosing regimen that was previously identified to be maximally cardioprotective, to drive tumor cell PD models. The resulting simulations showed that a 10:1 DEX:DOX dose ratio over three cycles of Q3W regimen of DOX results in comparable efficacy based on MDA-MB-468 (additive effect) estimates and lower efficacy based on JIMT-1 (antagonistic effect) estimates for DOX + DEX combination as compared to DOX alone. Thus, our developed cell-based PD models can be used to simulate different scenarios and better design preclinical studies to further optimize DOX and DEX combinations.
PubMed: 37927589
DOI: 10.3389/fphar.2023.1239141 -
Cancer Medicine Dec 2023To assess the occurrence of cardiotoxicity in patients with tumors receiving anthracycline-based chemotherapy, especially for sarcomas.
Evaluation of cardiotoxicity of anthracycline-containing chemotherapy regimens in patients with bone and soft tissue sarcomas: A study of the FDA adverse event reporting system joint single-center real-world experience.
OBJECTIVES
To assess the occurrence of cardiotoxicity in patients with tumors receiving anthracycline-based chemotherapy, especially for sarcomas.
METHODS
This study summarized the types and frequency of adverse events (AEs) for three anthracyclines from the FDA adverse event reporting system (FAERS) database. FAERS data from January 2004 to June 2022 were collected and analyzed. Disproportionality analyses, logistic regression, and descriptive analysis were used to compare the differences in cardiac disorders. A retrospective cohort study was conducted in a single center between December 2008 and May 2022. Our hospital-treated patients with bone and soft tissue sarcomas (BSTSs) with anthracycline-containing chemotherapy were analyzed. Serum markers, echocardiography, and electrocardiography have been used to evaluate cardiotoxic events.
RESULTS
One hundred thousand and seventy-five AE reports were obtained for doxorubicin (ADM), epirubicin (EPI), and liposome doxorubicin (L-ADM) from the FAERS database. ADM (OR = 3.1, p < 0.001), EPI (OR = 1.5, p < 0.001), and sarcomas (OR = 1.8, p < 0.001) may increase the probability of cardiac disorders. Cardiac failure, cardiotoxicity, and cardiomyopathy were anthracyclines' top 3 frequent AEs. Among patients receiving ADM-containing therapy, those with ADM applied at doses ≥75 mg/m /cycle were more likely to develop cardiac disorders than the other subgroups (OR = 3.5, p < 0.001). Patients younger than 18 are more likely to benefit from dexrazoxane prevention of cardiac failure. Six hundred and eighty-three patients with BSTSs receiving anthracycline-based chemotherapy were analyzed in our center. Patients receiving ADM-containing chemotherapy were likelier to experience abnormalities in serum troponin-T and left ventricular ejection fraction (p < 0.05). 2.0% (6/300) of patients receiving ADM-containing chemotherapy required adjustment of the chemotherapy regimen because of cardiotoxicity, whereas none were in the EPI or L-ADM groups.
CONCLUSIONS AND RELEVANCE
Among patients receiving anthracycline-containing therapy, patients with BSTSs were more likely to develop cardiac disorders than other tumors. In addition, patients with BSTSs receiving ADM chemotherapy had a higher likelihood of cardiotoxic events than those receiving EPI or L-ADM.
Topics: Humans; Anthracyclines; Cardiotoxicity; Retrospective Studies; Stroke Volume; Ventricular Function, Left; Antibiotics, Antineoplastic; Heart Diseases; Heart Failure; Doxorubicin; Epirubicin; Sarcoma; Soft Tissue Neoplasms
PubMed: 38054208
DOI: 10.1002/cam4.6730