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Frontiers in Cardiovascular Medicine 2022Anthracyclines remain an essential component of the treatment of many hematologic and solid organ malignancies, but has important implications on cardiovascular disease.... (Review)
Review
Anthracyclines remain an essential component of the treatment of many hematologic and solid organ malignancies, but has important implications on cardiovascular disease. Anthracycline induced cardiotoxicity (AIC) ranges from asymptomatic LV dysfunction to highly morbid end- stage heart failure. As cancer survivorship improves, the detection and treatment of AIC becomes more crucial to improve patient outcomes. Current treatment modalities for AIC have been largely extrapolated from treatment of conventional heart failure, but developing effective therapies specific to AIC is an area of growing research interest. This review summarizes the current evidence behind the use of neurohormonal agents, dexrazoxane, and resynchronization therapy in AIC, evaluates the clinical outcomes of advanced therapy and heart transplantation in AIC, and explores future horizons for treatment utilizing gene therapy, stem cell therapy, and mechanism-specific targets.
PubMed: 35528842
DOI: 10.3389/fcvm.2022.863314 -
Pharmaceutical Biology Dec 2022Shengmai injection (SMI) has been used to treat heart failure.
CONTEXT
Shengmai injection (SMI) has been used to treat heart failure.
OBJECTIVE
This study determines the molecular mechanisms of SMI against cardiotoxicity caused by doxorubicin (DOX).
MATERIALS AND METHODS
, DOX (15 mg/kg) was intraperitoneally injected in model, Dex (dexrazoxane), SMI-L (2.7 mL/kg), SMI-M (5.4 mL/kg), and SMI-H (10.8 mL/kg) for 7 consecutive days. Hematoxylin-eosin (HE) and Masson staining were used to evaluate histological changes, and cardiomyocyte apoptosis was identified using TdT-mediated dUTP nick-end labelling (TUNEL). Enzymatic indexes were determined. mRNA and protein expressions were analysed through RT-qPCR and Western blotting. , H9c2 cells were divided into control group, model group (2 mL 1 μM DOX), SMI group, ML385 group, and SMI + ML385 group, the intervention lasted for 24 h. mRNA and protein expressions were analysed.
RESULTS
SMI markedly improved cardiac pathology, decreased cardiomyocyte apoptosis, increased creatine kinase (CK), lactate dehydrogenase (LDH), malondialdehyde (MDA), decreased superoxide dismutase (SOD). Compared with the model group, the protein expression of nuclear factor erythroid2-related factor 2 (Nrf2) (SMI-L: 2.42-fold, SMI-M: 2.67-fold, SMI-H: 3.07-fold) and haem oxygenase-1(HO-1) (SMI-L: 1.64-fold, SMI-M: 2.01-fold, SMI-H: 2.19-fold) was increased and the protein expression of kelch-like ECH-associated protein 1 (Keap1) (SMI-L: 0.90-fold, SMI-M: 0.77-fold, SMI-H: 0.66-fold) was decreased in SMI groups and Dex group . Additionally, SMI dramatically inhibited apoptosis, decreased CK, LDH and MDA levels, and enhanced SOD activity. Our results demonstrated that SMI reduced DOX-induced cardiotoxicity via activation of the Nrf2/Keap1 signalling pathway.
CONCLUSIONS
This study revealed a new mechanism by which SMI alleviates DOX-induced 45 cardiomyopathy by modulating the Nrf2/Keap1 signal pathway.
Topics: Animals; Apoptosis; Cardiotoxicity; Cells, Cultured; Doxorubicin; Drug Combinations; Drugs, Chinese Herbal; Kelch-Like ECH-Associated Protein 1; Molecular Docking Simulation; Myocardium; NF-E2-Related Factor 2; Rats; Rats, Sprague-Dawley; Signal Transduction
PubMed: 35298357
DOI: 10.1080/13880209.2022.2046801 -
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 -
European Heart Journal Supplements :... Oct 2021Prevention of left ventricular dysfunction predominantly induced by anthracyclines and/or trastuzumab still represents a challenge for cardio-oncology today. Indeed,...
Prevention of left ventricular dysfunction predominantly induced by anthracyclines and/or trastuzumab still represents a challenge for cardio-oncology today. Indeed, this complication threatens to limit the significant gain in cancer survival achieved to date. Oncology strategies with cumulative dose limitation, continuous infusion, dexrazoxane, and liposomal formulations have been shown to decrease the risk of anthracycline cardiotoxicity. The preventive use of ace inhibitors, sartans, and/or beta-blockers has not yet provided convincing evidence and the positive effect on left ventricular ejection fraction decline appears poor without a clear clinical relevance. Assessment of the cardiovascular risk profile is a key aspect of the baseline evaluation of any patient scheduled for cancer therapy. Control and/or correction of modifiable cardiovascular risk factors is the first form of primary prevention of cardiotoxicity. It will be necessary to select populations at higher risk of developing cardiac dysfunction, identify patients genetically predisposed to develop cardiotoxicity in order to build the most appropriate strategies to correctly and timely target cardioprotective therapies.
PubMed: 35233212
DOI: 10.1093/eurheartj/suab085 -
Frontiers in Cell and Developmental... 2022Doxorubicin (DOX) is one of the most effective chemotherapeutic agents. However, its clinical use is limited due to the severe risk of cardiotoxicity. One of the...
Doxorubicin (DOX) is one of the most effective chemotherapeutic agents. However, its clinical use is limited due to the severe risk of cardiotoxicity. One of the hallmarks of doxorubicin-induced cardiotoxicity (DICT) is the cascade of mitophagy deficiency-mitochondrial oxidative injury-apoptosis, while so far, there is no preventive strategy for alleviating DICT by targeting this molecular mechanism. Excitedly, based on our previous drug screen in DICT zebrafish model, harpagoside (HAR) showed dramatic anti-DICT efficacy superior to dexrazoxane (DXZ) only cardioprotectant approved by FDA. Therefore, its pharmacological effects and molecular mechanism on DICT mouse and rat cardiomyocytes were further discussed. , HAR significantly improved cardiac function and myocardial structural lesions with concomitant of diminished mitochondrial oxidative damage and recovered mitophagy flux. In parallel, HAR protected mitophagy and mitochondria homeostasis, and repressed apoptosis . Intriguingly, both nutlin-3 (agonist of p53) and Parkin siRNA reversed these protective effects of HAR. Additional data, including fluorescence colocalization of Parkin and MitoTracker and mt-Keima for the detection of mitophagy flux and coimmunoprecipitation of p53 and Parkin, showed that HAR promoted Parkin translocation to mitochondria and substantially restored Parkin-mediated mitophagy by inhibiting the binding of p53 and Parkin. Importantly, the results of the cell viability demonstrated that cardioprotective effect of HAR did not interfere with anticancer effect of DOX on MCF-7 and HepG2 cells. Our research documented p53-Parkin-mediated cascade of mitophagy deficiency-mitochondrial dyshomeostasis-apoptosis as a pathogenic mechanism and druggable pathway and HAR as a cardioprotection on DICT by acting on novel interaction between p53 and Parkin.
PubMed: 35223843
DOI: 10.3389/fcell.2022.813370 -
Oxidative Medicine and Cellular... 2022The therapeutic efficacy of anthracycline antibiotic, doxorubicin (Dox), is hampered due to the dose-dependent cardiotoxicity. The objective of the study was to explore...
The therapeutic efficacy of anthracycline antibiotic, doxorubicin (Dox), is hampered due to the dose-dependent cardiotoxicity. The objective of the study was to explore the counteraction of aqueous bark extract of in Dox-induced cardiotoxicity in Wistar rats. The acute and subchronic toxicity study performed with 2.0 g/kg of the plant extract revealed biochemical and haematological parameters to be within the physiological range, and no histological alterations were observed in any organs isolated. Screening of plant extract for the protection of the myocardium from Dox-induced oxidative stress, inflammation, and apoptosis was performed on five groups of rats: control, plant extract control, Dox control (distilled water (D.HO) 2 weeks + on the 11 day single injection of Dox, 18 mg/kg), plant + Dox (2.0 g/kg plant extract 2 weeks + on the 11 day Dox, 18 mg/kg), and positive control, dexrazoxane. A significant increase in cardiac biomarkers and lipid peroxidation ( < 0.001) and a significant decrease in antioxidant parameters ( < 0.001) were observed in the Dox control group. All these parameters were reversed significantly ( < 0.05) in the plant-pretreated group. The histopathological assessment of myocardial damage provided supportive evidence for the biochemical results obtained. Inflammatory markers, myeloperoxidase, expression of TNF and caspase-3, and DNA fragmentation (TUNEL positive nuclei) were significantly elevated ( < 0.05), and expression of Bcl-2 was significantly decreased ( < 0.05) in the Dox control; however, all these parameters were significantly reversed in the plant extract-treated group. In conclusion, the aqueous bark extract of (2.0 g/kg) has the ability to attenuate the Dox-induced oxidative stress, inflammation, apoptosis, and DNA fragmentation in Wistar rats.
Topics: Animals; Antibiotics, Antineoplastic; Antioxidants; Apoptosis; Cardiotonic Agents; Cardiotoxicity; DNA Fragmentation; Dose-Response Relationship, Drug; Doxorubicin; Inflammation; Myocytes, Cardiac; Oxidative Stress; Plant Bark; Plant Extracts; Rats; Rats, Wistar; Rubiaceae
PubMed: 35198093
DOI: 10.1155/2022/1714841 -
Biomedicine & Pharmacotherapy =... Apr 2022Cardiotoxicity remains the most common reason for failure during drug development. Recently, the zebrafish (Danio rerio) model has emerged for the evaluation of...
Cardiotoxicity remains the most common reason for failure during drug development. Recently, the zebrafish (Danio rerio) model has emerged for the evaluation of drug-dependent cardiotoxicity and for the identification of cardioprotective molecules. However, it remains unknown how closely the zebrafish-based results may be translated to humans. To tackle this issue, we established embryonic zebrafish models of doxorubicin-, adrenaline- and terfenadine-induced cardiotoxicity with unified dosing regimen which eventually enabled head-to-head comparison of the drugs. Subsequently, we determined whether human cardioprotective medications - dexrazoxane, metoprolol, carvedilol and valsartan - are able to manage heart dysfunction in zebrafish. Our results indicated that doxorubicin, adrenaline and terfenadine elicited overt signs of cardiotoxicity in fish, and we further showed that the blockade of the renin-angiotensin system and, to a lesser extent, β-adrenergic system, ameliorated the heart disease in zebrafish. From the drug development standpoint, our work opens the possibility to determine the cardiovascular properties of tested compounds using the rapid and affordable zebrafish model.
Topics: Animals; Cardiomyopathies; Cardiotoxicity; Carvedilol; Doxorubicin; Zebrafish
PubMed: 35158142
DOI: 10.1016/j.biopha.2022.112695 -
Cureus Nov 2021Pediatric cancers are a common cause of childhood morbidity. As a result, chemotherapeutic regimens have been designed to target childhood cancers. These medications are... (Review)
Review
Pediatric cancers are a common cause of childhood morbidity. As a result, chemotherapeutic regimens have been designed to target childhood cancers. These medications are necessary to treat pediatric cancers, however, oncology management options are accompanied by multiple negative and potentially fatal adverse effects. Although anthracyclines are the most commonly used chemotherapeutic agents associated with cardiotoxicity, we also explore other chemotherapeutic drugs used in children that can potentially affect the heart. Genetic variations resulting in single nucleotide polymorphism (SNP) have the propensity to modify the cardiotoxic effects of the chemotherapy drugs. The clinical presentation of the cardiac effects can vary from arrhythmias and heart failure to completely asymptomatic. A range of imaging studies and laboratory investigations can protect the heart from severe outcomes. The physiology of the heart and the effect of drugs in children vary vividly from adults; therefore, it is crucial to study the cardiotoxic effect of chemotherapy drugs in the pediatric population. This review highlights the potential contributing factors for cardiotoxicity in the pediatric population and discusses the identification and management options.
PubMed: 34976454
DOI: 10.7759/cureus.19658 -
Hematology. American Society of... Dec 2021Anthracycline chemotherapy remains an integral component of modern pediatric acute myeloid leukemia (AML) regimens and is often delivered at high doses to maximize...
Anthracycline chemotherapy remains an integral component of modern pediatric acute myeloid leukemia (AML) regimens and is often delivered at high doses to maximize cancer survival. Unfortunately, high-dose anthracyclines are associated with a significant risk of cardiotoxicity, which may result in early and/or long-term left ventricular systolic dysfunction and heart failure. Moreover, the development of cardiotoxicity during pediatric AML therapy is associated with lower event-free and overall survival, which may be partially attributable to incomplete anthracycline delivery. A combined strategy of primary cardioprotection and close cardiac monitoring can maximize chemotherapy delivery while reducing the toxicity of intensive AML therapy. Primary cardioprotection using dexrazoxane reduces short-term cardiotoxicity without compromising cancer survival. Liposomal anthracycline formulations, which are under active investigation, have the potential to mitigate cardiotoxicity while also improving antitumor efficacy. Primary cardioprotective strategies may reduce but not eliminate the risk of cardiotoxicity; therefore, close cardiac monitoring is also needed. Standard cardiac monitoring consists of serial echocardiographic assessments for left ventricular ejection fraction decline. Global longitudinal strain has prognostic utility in cancer therapy-related cardiotoxicity and may be used as an adjunct assessment. Additional cardioprotective measures should be considered in response to significant cardiotoxicity; these include cardiac remodeling medications to support cardiac recovery and anthracycline dose interruption and/or regimen modifications. However, the withholding of anthracyclines should be limited to avoid compromising cancer survival. A careful approach to cardioprotection during AML therapy is critical to maximize the efficacy of leukemia treatment while minimizing the short- and long-term risks of cardiotoxicity.
Topics: Adolescent; Anthracyclines; Antineoplastic Agents; Cardiotonic Agents; Cardiotoxicity; Child; Dexrazoxane; Female; Heart; Humans; Leukemia, Myeloid, Acute
PubMed: 34889355
DOI: 10.1182/hematology.2021000268 -
Cancer Feb 2022The objective of this study was to examine long-term outcomes among children newly diagnosed with cancer who were treated in dexrazoxane-containing clinical trials. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The objective of this study was to examine long-term outcomes among children newly diagnosed with cancer who were treated in dexrazoxane-containing clinical trials.
METHODS
P9404 (acute lymphoblastic leukemia/lymphoma [ALL]), P9425 and P9426 (Hodgkin lymphoma), P9754 (osteosarcoma), and Dana-Farber Cancer Institute 95-01 (ALL) enrolled 1308 patients between 1996 and 2001: 1066 were randomized (1:1) to doxorubicin with or without dexrazoxane, and 242 (from P9754) were nonrandomly assigned to receive dexrazoxane. Trial data were linked with the National Death Index, the Organ Procurement and Transplantation Network, the Pediatric Health Information System (PHIS), and Medicaid. Osteosarcoma survivors from the Childhood Cancer Survivor Study (CCSS; n = 495; no dexrazoxane) served as comparators in subanalyses. Follow-up events were assessed with cumulative incidence, Cox regression, and Fine-Gray methods.
RESULTS
In randomized trials (cumulative prescribed doxorubicin dose, 100-360 mg/m ; median follow-up, 18.6 years), dexrazoxane was not associated with relapse (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.63-1.13), second cancers (HR, 1.19; 95% CI, 0.62-2.30), all-cause mortality (HR, 1.07; 95% CI, 0.78-1.47), or cardiovascular mortality (HR, 1.45; 95% CI, 0.41-5.16). Among P9754 patients (all exposed to dexrazoxane; cumulative doxorubicin, 450-600 mg/m ; median follow-up, 16.6-18.4 years), no cardiovascular deaths or heart transplantation occurred. The 20-year heart transplantation rate among CCSS osteosarcoma survivors (mean doxorubicin, 377 ± 145 mg/m ) was 1.6% (vs 0% in P9754; P = .13). Among randomized patients, serious cardiovascular outcomes (cardiomyopathy, ischemic heart disease, and stroke) ascertained by PHIS/Medicaid occurred less commonly with dexrazoxane (5.6%) than without it (17.6%; P = .02), although cardiomyopathy rates alone did not differ (4.4% vs 8.1%; P = .35).
CONCLUSIONS
Dexrazoxane did not appear to adversely affect long-term mortality, event-free survival, or second cancer risk.
Topics: Child; Dexrazoxane; Doxorubicin; Follow-Up Studies; Hodgkin Disease; Humans; Outcome Assessment, Health Care; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 34644414
DOI: 10.1002/cncr.33974