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Frontiers in Pharmacology 2020The clinical use of Doxorubicin (Dox) is significantly limited by its dose-dependent cardiotoxic side effect. Accumulative evidence suggests that the use of flavonoids,...
BACKGROUND
The clinical use of Doxorubicin (Dox) is significantly limited by its dose-dependent cardiotoxic side effect. Accumulative evidence suggests that the use of flavonoids, such as the antioxidative Pinocembrin (Pin), could be effective in the prevention of Dox-induced cardiotoxicity. Accordingly, we investigated the ability of pinocembrin (Pin) to attenuate Dox-induced cardiotoxicity in an in vitro H9c2 cardiomyoblast model.
METHODOLOGY
The cardioprotective potential of Pin was established in H9c2 cells. Here, cells were treated with Dox (2μM), Dox (2μM) + Pin (1μM), and Dox (2μM) + Dexrazoxane (20μM) for 6 days. Thereafter, the safe co-administration of Pin with Dox, in a cancer environment, was investigated in MCF-7 breast cancer cells subjected to the same experimental conditions. Untreated cells served as the control. Subsequently, Pin's ability to attenuate Dox-mediated oxidative stress, impaired mitochondrial bioenergetics and potential, as well as aggravated apoptosis was quantified using biochemical assays.
RESULTS
The results demonstrated that co-treatment with Pin mitigates Dox-induced oxidative stress by alleviating the antioxidant enzyme activity of the H9c2 cells. Pin further reduced the rate of apoptosis and necrosis inferred by Dox by improving mitochondrial bioenergetics. Interestingly, Pin did not decrease the efficacy of Dox but, rather increased the rate of apoptosis and necrosis in Dox-treated MCF-7 cells.
CONCLUSION
The findings presented in this study showed, for the first time, that Pin attenuates Dox-induced cardiotoxicity without reducing its chemotherapeutic effect. We propose that additional studies, using in vivo models, should be conducted to further investigate Pin as a suitable candidate in the prevention of the cardiovascular dysfunction inferred by Dox administration.
PubMed: 32903793
DOI: 10.3389/fphar.2020.01172 -
Free Radical Biology & Medicine Nov 2020Ferroptosis is a reactive oxygen species (ROS)- and iron-dependent form of regulated cell death (RCD), playing critical roles in organ injury and targeting therapy of...
Ferroptosis is a reactive oxygen species (ROS)- and iron-dependent form of regulated cell death (RCD), playing critical roles in organ injury and targeting therapy of cancers. Previous studies have demonstrated that ferroptosis participates in the development of cardiomyopathy including cardiac hypertrophy, diabetic cardiomyopathy and doxorubicin-induced cardiotoxicity. However, the role of ferroptosis in sepsis-induced cardiac injury remains unclear. This study aimed to explore the role and underlying mechanism of ferroptosis on lipopolysaccharide (LPS)-induced cardiac injury. Mice were injected with LPS (10 mg/kg) for 12 h to generate experimental sepsis. Ferrostatin-1 (Fer-1) and Dexrazoxane (DXZ) were used to suppress ferroptosis of mice with sepsis-induced cardiac injury. LPS increased the levels of ferroptotic markers involving prostaglandin endoperoxide synthase 2 (PTGS2), malonaldehyde (MDA) and lipid ROS, apart from resulting in obvious mitochondria damage, which were alleviated by Fer-1 and DXZ. In vitro experiments showed that Fer-1 inhibited LPS-induced lipid peroxidation and injury of H9c2 myofibroblasts while erastin and sorafenib aggravated LPS-induced ferroptosis. Additionally, Fer-1 and DXZ improved survival rate and cardiac function of mice with sepsis. Mechanistically, LPS increased the expression of nuclear receptor coactivator 4 (NCOA4) and the level of intracellular Fe but decreased the level of ferritin. NCOA4 could directly interact with ferritin and degrade it in a ferritinophagy-dependent manner, which subsequently released a great amount of iron. Cytoplasmic Fe further activated the expression of siderofexin (SFXN1) on mitochondrial membrane, which in turn transported cytoplasmic Fe into mitochondria, giving rise to the production of mitochondrial ROS and ferroptosis. Based on these findings, we concluded that ferritinophagy-mediated ferroptosis is one of the critical mechanisms contributing to sepsis-induced cardiac injury. Targeting ferroptosis in cardiomyocytes may be a therapeutic strategy for preventing sepsis in the future.
Topics: Animals; Autophagy; Ferritins; Ferroptosis; Iron; Mice; Sepsis
PubMed: 32846217
DOI: 10.1016/j.freeradbiomed.2020.08.009 -
British Journal of Pharmacology Jul 2020Retraction: Spagnuolo, R., Recalcati, S., Tacchini, L., and Cairo, G. (2011), Role of hypoxia-inducible factors in the dexrazoxane-mediated protection of cardiomyocytes...
Retraction: Spagnuolo, R., Recalcati, S., Tacchini, L., and Cairo, G. (2011), Role of hypoxia-inducible factors in the dexrazoxane-mediated protection of cardiomyocytes from doxorubicin-induced toxicity. British Journal of Pharmacology, 163: 299-312. https://doi.org/10.1111/j.1476-5381.2011.01208.x The above article, published online on January 14, 2011, in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal's Editor-in-Chief, Professor Amrita Ahluwalia, the British Pharmacological Society, and John Wiley & Sons Ltd. The retraction has been agreed due to the duplication of Figures 1A and 3A, which overlap with figures appearing in another article published by the authors in the Journal of Leukocyte Biology in 2008. The authors state that due to the time elapsed, they are unable to provide evidence of the original data.
PubMed: 32512636
DOI: 10.1111/bph.15097 -
Annals of Palliative Medicine May 2020Observation indexes used to evaluate the effect of dexrazoxane-anthracycline combinations in breast cancer often only take into account the clinical symptoms, or left... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Observation indexes used to evaluate the effect of dexrazoxane-anthracycline combinations in breast cancer often only take into account the clinical symptoms, or left ventricular ejection fraction (LVEF), biomarkers [such as creatine kinase MB (CK-MB), brain natriuretic peptide (BNP) and cardiac troponin T (cTnT)], or tumor recurrence rate, improvement of autonomic nerve function or economic benefits. This study aimed to evaluate the effect of dexrazoxane on the changes of mechanical properties of right ventricular myocardium in patients who underwent pirarubicin chemotherapy with three-dimensional speckle-tracking imaging (3D-STI).
METHODS
A total of 64 breast cancer post-operation patients who received pirarubicin chemotherapy were randomly divided into two groups: the experimental group (with dexrazoxane added) and the control group (without dexrazoxane). The mechanical properties of the right ventricular myocardium were monitored by 3D-STI before and after chemotherapy. The levels of serum hypersensitive troponin I (hs-cTnI) and N-terminal B-type pro-natriuretic peptide (NT-proBNP) as well as conventional echocardiographic parameters were also measured.
RESULTS
After chemotherapy, right ventricular global longitudinal strain (RVGLS) and right ventricular global area strain (RVGAS) were significantly reduced in both groups (P<0.05). There was a significant difference between the two groups (P<0.05).
CONCLUSIONS
Dexrazoxane can alleviate the toxicity of pirarubicin in the right ventricular myocardium. 3D-STI is a potential new method for early and accurate evaluation of the mechanical properties and functional changes of the right ventricular myocardium.
Topics: Humans; Biomarkers; Breast Neoplasms; Dexrazoxane; Doxorubicin; Myocardium; Stroke Volume; Ventricular Function, Left
PubMed: 32498534
DOI: 10.21037/apm-20-1074 -
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 -
Evidence-based Complementary and... 2020Dose-dependent cardiotoxicity of doxorubicin may lead to irreversible congestive heart failure. Although multiple mechanisms are involved, generation of free radicals is...
Dose-dependent cardiotoxicity of doxorubicin may lead to irreversible congestive heart failure. Although multiple mechanisms are involved, generation of free radicals is the most commonly postulated mechanism. Therefore, free radical scavengers are considered as potential therapeutic agents. As leaves are a rich source of flavonoids and phenols, they have the ability to scavenge free radicals effectively. Therefore, the objective of this study was to investigate the cardioprotective potential of leaf extract against doxorubicin-induced cardiotoxicity in rats. Rats were randomly divided into five groups with 10 animals in each group. Doxorubicin was administered intraperitonially at 18 mg/kg while lyophilized plant extract was administered orally at 2 g/kg. Dexrazoxane, at 180 mg/kg, was used as the positive control. Cardiac damage of doxorubicin control was evident with a significant increase ( < 0.05) in cardiac troponin I, NT-pro BNP, AST, and LDH compared to the normal control. Plant-treated group showed cardioprotective effect by significantly reducing ( < 0.05) all of the above parameters compared to doxorubicin control ( < 0.05). Increased oxidative stress in doxorubicin control was evident with a significant reduction in reduced glutathione, glutathione reductase, glutathione peroxidase, total antioxidant capacity, superoxide dismutase, and catalase activity and a significant increase in lipid peroxidation compared to the control. Interestingly, treatment with leaf extract showed a significant increase in all of the above antioxidant parameters and a significant reduction in lipid peroxidation by showing an antioxidant effect. A significant increase in myeloperoxidase activity confirmed the increased inflammatory activity in doxorubicin control group whereas plant-treated group showed a significant reduction ( < 0.05) which expressed the anti-inflammatory effect of leaf extract. Doxorubicin-treated group showed histological evidence of extensive damage to the myocardium while plant-treated group showed a preserved myocardium with lesser degree of damage. Pretreatment with leaf extract may replenish cardiomyocytes with antioxidants and promote the defense against doxorubicin-induced cardiotoxicity.
PubMed: 32308710
DOI: 10.1155/2020/6023737 -
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 -
Cardio-oncology (London, England) 2020Continuous infusion of doxorubicin or dexrazoxane pre-treatment prior to bolus doxorubicin are proven strategies to protect against doxorubicin-induced cardiotoxicity....
BACKGROUND
Continuous infusion of doxorubicin or dexrazoxane pre-treatment prior to bolus doxorubicin are proven strategies to protect against doxorubicin-induced cardiotoxicity. Recently, global longitudinal peak systolic strain (GLS) measured with speckle tracking echocardiography (STE) and high-sensitivity troponin T (hs-TnT) have been validated as sensitive indicators of doxorubicin-induced cardiotoxicity. Here, we asked whether changes in hs-TnT and/or GLS can be detected in patients who were treated with continuous infusion of doxorubicin or pre-treated with dexrazoxane followed by bolus doxorubicin.
METHODS
Twenty-nine patients with newly diagnosed sarcoma were assigned to receive either 72-h doxorubicin infusion or dexrazoxane pre-treatment before bolus doxorubicin. Eight patients received dexrazoxane pre-treatment; eleven patients received continuous doxorubicin infusion; ten patients crossed over from continuous infusion to dexrazoxane. Bloods were collected for hs-TnT at baseline, 24 h or 72 h after initiation of doxorubicin treatment in each chemotherapy cycle. All blood samples were assayed in batch using hs-TnT kit from Roche diagnostics. 2D Echo and STE were performed before doxorubicin, after cycle 3, and at the end of chemotherapy.
RESULTS
Seven patients in the cross-over group have at least one hs-TnT measurement between 5 ng/L to 10 ng/L during and after chemotherapy. Ten patients have at least one hs-TnT measurement above 10 ng/ml during and after chemotherapy (six in dexrazoxane group, three in continuous infusion group, one in cross-over group). The average hs-TnT level increases with each additional cycle of doxorubicin treatment. Eight patients had a more than 5% reduction in LVEF at the end of chemotherapy (four in dexrazoxane group, three in continuous infusion group, and one in cross-over group). Four out of these eight patients had a change of GLS by more than 15% (three in the dexrazoxane group).
CONCLUSION
Elevation in hs-TnT levels were observed in more than 59% of patients who had received either continuous doxorubicin infusion or dexrazoxane pre-treatment before bolus doxorubicin. However, changes in LVEF and GLS were less frequently observed. Thus, continuous doxorubicin infusion or dexrazoxane pre-treatment do not completely ameliorate subclinical doxorubicin-induced cardiotoxicity as detected by more sensitive techniques.
PubMed: 32154027
DOI: 10.1186/s40959-019-0056-3 -
Cardio-oncology (London, England) 2019Cancer diagnostics and therapies have improved steadily over the last few decades, markedly increasing life expectancy for patients at all ages. However, conventional... (Review)
Review
Cancer diagnostics and therapies have improved steadily over the last few decades, markedly increasing life expectancy for patients at all ages. However, conventional and newer anti-neoplastic therapies can cause short- and long-term cardiotoxicity. The clinical implications of this cardiotoxicity become more important with the increasing use of cardiotoxic drugs. The implications are especially serious among patients predisposed to adverse cardiac effects, such as youth, the elderly, those with cardiovascular comorbidities, and those receiving additional chemotherapies or thoracic radiation. However, the optimal strategy for preventing and managing chemotherapy-induced cardiotoxicity remains unknown. The routine use of neurohormonal antagonists for cardioprotection is not currently justified, given the marginal benefits and associated adverse events, particularly with long-term use. The only United States Food and Drug Administration and European Medicines Agency approved treatment for preventing anthracycline-related cardiomyopathy is dexrazoxane. We advocate administering dexrazoxane during cancer treatment to limit the cardiotoxic effects of anthracycline chemotherapy.
PubMed: 32154024
DOI: 10.1186/s40959-019-0054-5 -
Cardio-oncology (London, England) 2019Dexrazoxane protects from lower-cumulative-dose doxorubicin cardiotoxicity, but the effect of dexrazoxane in children with sarcoma treated with higher-cumulative-dose...
BACKGROUND
Dexrazoxane protects from lower-cumulative-dose doxorubicin cardiotoxicity, but the effect of dexrazoxane in children with sarcoma treated with higher-cumulative-dose doxorubicin is unknown.
METHODS
We evaluated children with osteosarcoma (OS) on two Children's Oncology Group trials with higher dose doxorubicin (375-600 mg/m) preceded by dexrazoxane (10:1 dexrazoxane:doxorubicin dosing). They were evaluated after the minimum expected treatment time (METT), defined as 28 weeks. Cardiotoxicity was identified by echocardiography and serum N-terminal pro-brain natriuretic peptide (NT-proBNP). Second malignant neoplasm (SMN) data was collected.
RESULTS
All children had normal left ventricular (LV) systolic function as measured by LV fractional shortening and no heart failure. The end-diastolic septal thickness scores ( < 0.01) and LV mass scores ( < 0.01) were significantly smaller than normal for body-surface area in both sexes. The average LV mass scores were significantly smaller for girls ( < 0.01) and marginally smaller for boys ( = 0.06). Girls had significantly smaller LV end-diastolic dimension scores normalized to BSA ( < 0.01) compared to healthy controls and had significant increases in NT-proBNP. Four children developed SMNs as first events, a rate similar to historical controls.
CONCLUSIONS
Dexrazoxane prevented LV dysfunction and heart failure in children with OS receiving higher dose doxorubicin. However, LV structural changes were not fully prevented, especially in girls. As a result, hearts become abnormally small for body size, resulting in higher LV stress. Dexrazoxane did not increase the risk of SMN. Dexrazoxane should be used in this population, particularly for girls, to mitigate anthracycline-induced cardiotoxicity.
TRIAL REGISTRATIONS
ClinicalTrials.gov: NCT00003937 (P9754) registered 1 Nov 1999, and NCT00023998 (AOST0121) registered 13 Sept 2001.
PubMed: 32154021
DOI: 10.1186/s40959-019-0050-9