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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 -
Antioxidants & Redox Signaling Jul 2022Cancer patients treated with anthracyclines are susceptible to atrial fibrillation (AF), while the mechanisms remain unclear. Due to sudden and unpredictable features,...
Cancer patients treated with anthracyclines are susceptible to atrial fibrillation (AF), while the mechanisms remain unclear. Due to sudden and unpredictable features, prediction of anthracycline-induced AF at early phase is difficult. Clinically, we tested whether anthracycline-induced early atrial remodeling in patients could be detected by echocardiography. Experimentally, we investigated the mechanisms of doxorubicin-induced atrial remodeling and AF in mice, and the protective effects of dexrazoxane and antioxidants. Postsurgery breast cancer patients with an anthracycline-containing or anthracycline exclusion regimen were recruited for echocardiography before chemotherapy, and 3 and 6 months after chemotherapy. Mice were injected with doxorubicin or vehicle (5 mg/kg/week, 4 weeks), and left atrial diameter, electrical transmission, and AF inducibility were measured. Meanwhile, the level of reactive oxygen species (ROS), activity of antioxidant enzymes, cardiomyocyte size, vacuolization, inflammation, and fibrosis were also measured in mouse atria. The therapeutic effects of dexrazoxane and antioxidants on doxorubicin-induced changes in the aforementioned parameters were also determined. While ventricular parameters and functions were unchanged in cancer patients receiving anthracyclines before and after chemotherapy, left atrial reservoir and conduit function were decreased at 3 months postchemotherapy prechemotherapy. Doxorubicin-induced susceptibility to AF occurred in mice before onset of ventricular dysfunction. Doxorubicin-induced AF was inducing structural remodeling (cardiomyocyte death, hypotrophy, and vacuolization) and electrical remodeling (reduction and redistribution of connexin 43) in atria, which was effectively prevented by dexrazoxane or antioxidants through inhibiting ROS generation or enhancing ROS elimination. AF inducibility was induced after doxorubicin injection, which can be inhibited by repressing the ROS level. . 37, 19-39. The Clinical Trial Registration number is PJ-KS-KY-2019-73.
Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Antioxidants; Atrial Fibrillation; Atrial Remodeling; Breast Neoplasms; Cardiotoxicity; Dexrazoxane; Doxorubicin; Female; Humans; Mice; Reactive Oxygen Species
PubMed: 35081742
DOI: 10.1089/ars.2021.0002 -
Pharmacology 2022Doxorubicin (DOX), an anthracycline antitumor agent, has been widely used against various solid tumors and hematological malignancies. However, the clinical application...
INTRODUCTION
Doxorubicin (DOX), an anthracycline antitumor agent, has been widely used against various solid tumors and hematological malignancies. However, the clinical application of DOX is restricted by its multiple organ toxicity including nephrotoxicity. This study investigated the protective effects and mechanisms of dexrazoxane (DZR) against DOX-induced nephropathy in rats.
METHODS
Male Sprague Dawley rats received 2.5 mg/kg DOX once a week for 5 consecutive weeks. 24-h urinary protein and renal function injury biomarkers were determined to evaluate the renal function. Histopathological changes and glomerulosclerosis were examined by hematoxylin and eosin and periodic acid-Schiff staining. The change of renal ultrastructure in the DOX-induced rats was observed by the electron microscopy. The renal apoptosis was detected by TUNEL staining and measured the protein expression of Caspase-3, Bcl-2, and Bax. Renal interstitial fibrosis was determined by Masson staining and immunohistochemistry examination. The levels of vimentin, alpha-smooth muscle actin (α-SMA), and transforming growth factor β (TGF-β) in kidney tissue were detected by Western blot.
RESULTS
DZR pretreatment markedly raised the survival rate and improved the renal dysfunction in DOX-treated rats. DZR ameliorated DOX-induced histopathological lesion of glomerular and tubular and apoptosis. DZR restored the oxidant/antioxidant balance via regulating the levels of MDA, SOD, and TAC. DZR reduced DOX-induced collagen IV deposition and renal interstitial fibrosis and downregulated the fibrosis-related protein expressions of vimentin, α-SMA, and TGF-β1.
CONCLUSION
Our results suggest DZR exerted its protective effects against DOX-induced nephropathy through inhibition of lipid peroxidation, apoptosis, and fibrosis.
Topics: Animals; Antibiotics, Antineoplastic; Dexrazoxane; Doxorubicin; Fibrosis; Kidney; Kidney Diseases; Male; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta1
PubMed: 35021174
DOI: 10.1159/000521220 -
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 -
Expert Review of Cardiovascular Therapy Nov 2021Over the past five decades, the diagnosis and management of children with various malignancies have improved tremendously. As a result, an increasing number of children... (Review)
Review
INTRODUCTION
Over the past five decades, the diagnosis and management of children with various malignancies have improved tremendously. As a result, an increasing number of children are long-term cancer survivors. With improved survival, however, has come an increased risk of treatment-related cardiovascular complications that can appear decades later.
AREAS COVERED
This review discusses the pathophysiology, epidemiology and effects of treatment-related cardiovascular complications from anthracyclines and radiotherapy in pediatric lymphoma survivors. There is a paucity of evidence-based recommendations for screening for and treatment of cancer therapy-induced cardiovascular complications. We discuss current preventive measures and strategies for their treatment.
EXPERT OPINION
Significant cardiac adverse effects occur due to radiation and chemotherapy received by patients treated for lymphoma. Higher lifetime cumulative doses, female sex, longer follow-up, younger age, and preexisting cardiovascular disease are associated with a higher incidence of cardiotoxicity. With deeper understanding of the mechanisms of these adverse cardiac effects and identification of driver mutations causing these effects, personalized cancer therapy to limit cardiotoxic effects while ensuring an adequate anti-neoplastic effect would be ideal. In the meantime, expanding the use of cardioprotective agents with the best evidence such as dexrazoxane should be encouraged and further studied.
Topics: Anthracyclines; Antineoplastic Agents; Cardiotoxicity; Child; Female; Humans; Lymphoma; Neoplasms; Risk Factors; Survivors
PubMed: 34958622
DOI: 10.1080/14779072.2021.2013811 -
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 -
Clinical Science (London, England :... Jan 2022Angiotensin-converting enzyme inhibitors (ACEis) have been used to treat anthracycline (ANT)-induced cardiac dysfunction, and they appear beneficial for secondary...
Angiotensin-converting enzyme inhibitors (ACEis) have been used to treat anthracycline (ANT)-induced cardiac dysfunction, and they appear beneficial for secondary prevention in high-risk patients. However, it remains unclear whether they truly prevent ANT-induced cardiac damage and provide long-lasting cardioprotection. The present study aimed to examine the cardioprotective effects of perindopril on chronic ANT cardiotoxicity in a rabbit model previously validated with the cardioprotective agent dexrazoxane (DEX) with focus on post-treatment follow-up (FU). Chronic cardiotoxicity was induced by daunorubicin (DAU; 3 mg/kg/week for 10 weeks). Perindopril (0.05 mg/kg/day) was administered before and throughout chronic DAU treatment. After the completion of treatment, significant benefits were observed in perindopril co-treated animals, particularly full prevention of DAU-induced mortality and prevention or significant reductions in cardiac dysfunction, plasma cardiac troponin T (cTnT) levels, morphological damage, and most of the myocardial molecular alterations. However, these benefits significantly waned during 3 weeks of drug-free FU, which was not salvageable by administering a higher perindopril dose. In the longer (10-week) FU period, further worsening of left ventricular function and morphological damage occurred together with heart failure (HF)-related mortality. Continued perindopril treatment in the FU period did not reverse this trend but prevented HF-related mortality and reduced the severity of the progression of cardiac damage. These findings contrasted with the robust long-lasting protection observed previously for DEX in the same model. Hence, in the present study, perindopril provided only temporary control of ANT cardiotoxicity development, which may be associated with the lack of effects on ANT-induced and topoisomerase II β (TOP2B)-dependent DNA damage responses in the heart.
Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antibiotics, Antineoplastic; Cardiotoxicity; Daunorubicin; Heart Diseases; Heart Failure; Male; Perindopril; Rabbits; Troponin T
PubMed: 34878093
DOI: 10.1042/CS20210836 -
Journal of Oncology Pharmacy Practice :... Apr 2022For young adult patients with acute leukemia, both the efficacy and cardiotoxicity of anthracycline-based regimens have been documented. We report the case of a patient...
INTRODUCTION
For young adult patients with acute leukemia, both the efficacy and cardiotoxicity of anthracycline-based regimens have been documented. We report the case of a patient with severe cardiomyopathy, mechanically supported by a left ventricular assist device (LVAD), who subsequently developed Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph + ALL). To our knowledge, this is the first report of anthracycline administration in a patient with heart failure requiring mechanical support.
CASE REPORT
Our 27-year-old female patient was diagnosed with Ph + B-ALL as part of workup for leukocytosis. Past medical history included non-ischemic cardiomyopathy with a left ventricular ejection fraction of 30-35% and moderate-severe right ventricular dysfunction, for which LVAD had been placed 4 years previously.
MANAGEMENT & OUTCOME
After shared decision-making and multidisciplinary discussions, we felt that hyperfractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone alternating with cytarabine and high-dose methotrexate in addition to ponatinib (HyperCVAD-ponatinib) best balanced the patient's goals for aggressive treatment with the potential for rapid and durable remissions. The patient received a single reduced dose of doxorubicin alongside dexrazoxane with her first cycle of HyperCVAD-ponatinib. She attained a complete molecular response 22 days later and remains in remission (with stable cardiac function) 30 months later on maintenance therapy.
DISCUSSION
In conclusion, LVAD placement is not an absolute contra-indication to anthracyclines if such therapies offer the best opportunity for a durable response.
Topics: Adult; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cardiomyopathies; Doxorubicin; Female; Humans; Leukemia, Myeloid, Acute; Stroke Volume; Ventricular Function, Left; Young Adult
PubMed: 34846217
DOI: 10.1177/10781552211062148 -
The International Journal of... Apr 2022Doxorubicin leads to dose-dependent cardiotoxicity in childhood acute lymphoblastic leukemia (ALL) survivors. The first aim was to propose a contour-based estimation of...
Doxorubicin leads to dose-dependent cardiotoxicity in childhood acute lymphoblastic leukemia (ALL) survivors. The first aim was to propose a contour-based estimation of T1 and T2 relaxation times based on the myocardial area, while our second aim was to evaluate native T1, post-gadolinium T1 and T2 relaxation time sensitivity to detect myocardial changes. A total of 84 childhood ALL survivors were stratified in regard to their prognostic risk groups: standard risk (SR), n = 20), high-risk with and without dexrazoxane (HR + DEX, n = 39 and HR, n = 25). Survivors' mean age was of 22.0 ± 6.9 years, with a mean age at cancer diagnosis of 8.0 ± 5.2 years. CMR acquisitions were performed on a 3 T MRI system and included an ECG-gated 3(3)3(3)5 MOLLI sequence for T1 mapping and an ECG-gated T2-prepared TrueFISP sequence for T2 mapping. Myocardial contours were semi-automatically segmented using an interactive implementation of cubic Bezier curves. We found excellent repeatability between operators for native T1 (ICC = 0.91), and good repeatability between operators for post-gadolinium T1 (ICC = 0.84) and T2 (ICC = 0.79). Bland and Altman tests demonstrated a strong agreement between our contour-based method and images analyzed using the CVI42 software on the measure of native T1, post-gadolinium T1, and T2. No significant differences between survivors' prognostic risk groups in native T1 were reported, while we observed significant differences between survivors' prognostic risk groups in post-gadolinium T1 and T2. Significant differences were observed between male and female survivors. Differences between groups were also observed in partition coefficients, but no significant differences were observed between male and female survivors. The use of CMR parameters with native T1, post-gadolinium T1, and T2 allowed to show that survivors at a high-risk prognostic were more exposed to doxorubicin-related cardiotoxicity than those who were at a standard risk prognostic or who received dexrazoxane treatments.
PubMed: 34821983
DOI: 10.1007/s10554-021-02472-0