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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 -
Cardiovascular Drugs and Therapy Feb 2017Anthracycline chemotherapy maintains a prominent role in treating many forms of cancer. Cardiotoxic side effects limit their dosing and improved cancer outcomes expose... (Review)
Review
Anthracycline chemotherapy maintains a prominent role in treating many forms of cancer. Cardiotoxic side effects limit their dosing and improved cancer outcomes expose the cancer survivor to increased cardiovascular morbidity and mortality. The basic mechanisms of cardiotoxicity may involve direct pathways for reactive oxygen species generation and topoisomerase 2 as well as other indirect pathways. Cardioprotective treatments are few and those that have been examined include renin angiotensin system blockade, beta blockers, or the iron chelator dexrazoxane. New treatments exploiting the ErbB or other novel pro-survival pathways, such as conditioning, are on the cardioprotection horizon. Even in the forthcoming era of targeted cancer therapies, the substantial proportion of today's anthracycline-treated cancer patients may become tomorrow's cardiac patient.
Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Cardiotoxicity; Cardiovascular Agents; Cytoprotection; Heart Diseases; Humans; Myocytes, Cardiac; Risk Factors; Signal Transduction; Time Factors; Troponin
PubMed: 28185035
DOI: 10.1007/s10557-016-6711-0 -
World Journal of Clinical Oncology Feb 2016Chemotherapy extravasation remains an accidental complication of chemotherapy administration and may result in serious damage to patients. We review in this article the... (Review)
Review
Chemotherapy extravasation remains an accidental complication of chemotherapy administration and may result in serious damage to patients. We review in this article the clinical aspects of chemotherapy extravasation and latest advances in definitions, classification, prevention, management and guidelines. We review the grading of extravasation and tissue damage according to various chemotherapeutic drugs and present an update on treatment and new antidotes including dexrazoxane for anthracyclines extravasation. We highlight the importance of education and training of the oncology team for prevention and prompt pharmacological and non-pharmacological management and stress the availability of new antidotes like dexrazoxane wherever anthracyclines are being infused.
PubMed: 26862492
DOI: 10.5306/wjco.v7.i1.87 -
Proceedings of the National Academy of... Feb 2019Heart disease is the leading cause of death worldwide. A key pathogenic factor in the development of lethal heart failure is loss of terminally differentiated...
Heart disease is the leading cause of death worldwide. A key pathogenic factor in the development of lethal heart failure is loss of terminally differentiated cardiomyocytes. However, mechanisms of cardiomyocyte death remain unclear. Here, we discovered and demonstrated that ferroptosis, a programmed iron-dependent cell death, as a mechanism in murine models of doxorubicin (DOX)- and ischemia/reperfusion (I/R)-induced cardiomyopathy. In canonical apoptosis and/or necroptosis-defective , , or mice, DOX-treated cardiomyocytes showed features of typical ferroptotic cell death. Consistently, compared with dexrazoxane, the only FDA-approved drug for treating DOX-induced cardiotoxicity, inhibition of ferroptosis by ferrostatin-1 significantly reduced DOX cardiomyopathy. RNA-sequencing results revealed that heme oxygenase-1 () was significantly up-regulated in DOX-treated murine hearts. Administering DOX to mice induced cardiomyopathy with a rapid, systemic accumulation of nonheme iron via heme degradation by Nrf2-mediated up-regulation of Hmox1, which effect was abolished in -deficent mice. Conversely, zinc protoporphyrin IX, an Hmox1 antagonist, protected the DOX-treated mice, suggesting free iron released on heme degradation is necessary and sufficient to induce cardiac injury. Given that ferroptosis is driven by damage to lipid membranes, we further investigated and found that excess free iron accumulated in mitochondria and caused lipid peroxidation on its membrane. Mitochondria-targeted antioxidant MitoTEMPO significantly rescued DOX cardiomyopathy, supporting oxidative damage of mitochondria as a major mechanism in ferroptosis-induced heart damage. Importantly, ferrostatin-1 and iron chelation also ameliorated heart failure induced by both acute and chronic I/R in mice. These findings highlight that targeting ferroptosis serves as a cardioprotective strategy for cardiomyopathy prevention.
Topics: Animals; Apoptosis; Cardiomyopathies; Doxorubicin; Heme; Heme Oxygenase-1; Iron; Lipid Peroxidation; Mice; Mice, Knockout; Mitochondria, Heart; Myocytes, Cardiac; NF-E2-Related Factor 2; Reperfusion Injury; Up-Regulation
PubMed: 30692261
DOI: 10.1073/pnas.1821022116 -
Biomedicine & Pharmacotherapy =... Dec 2022Doxorubicin (DOX), as a kind of chemotherapy agent with remarkable therapeutic effect, can be used to treat diverse malignant tumors clinically. Dose-dependent... (Review)
Review
Doxorubicin (DOX), as a kind of chemotherapy agent with remarkable therapeutic effect, can be used to treat diverse malignant tumors clinically. Dose-dependent cardiotoxicity is the most serious adverse reaction after DOX treatment, which eventually leads to cardiomyopathy and greatly limits the clinical application of DOX. DOX-induced cardiomyopathy is not a result of a single mechanistic action, and multiple mechanisms have been discovered and demonstrated experimentally, such as oxidative stress, inflammation, mitochondrial damage, calcium homeostasis disorder, ferroptosis, autophagy and apoptosis. Dexrazoxane (DEX) is the only protective agent approved by FDA for the treatment of DOX cardiomyopathy, but its clinical treatment still has some limitations. Therefore, we need to find other effective therapeutic drugs as soon as possible. In this paper, the drugs that effectively improve cardiomyopathy in recent years are mainly described from the aspects of natural drugs, endogenous substances, new dosage forms, herbal medicines, chemical modification and marketed drugs. The aim of the present study is to evaluate the effects of these drugs on DOX-induced anticancer and cardiomyopathy curative effects, so as to provide some reference value for clinical treatment of DOX-induced cardiomyopathy in the future.
Topics: Humans; Myocytes, Cardiac; Cardiotoxicity; Doxorubicin; Cardiomyopathies; Apoptosis; Oxidative Stress
PubMed: 36279722
DOI: 10.1016/j.biopha.2022.113903 -
Journal of Clinical Oncology : Official... Apr 2023For survivors of childhood cancer treated with doxorubicin, dexrazoxane is cardioprotective for at least 5 years. However, longer-term data are lacking.
PURPOSE
For survivors of childhood cancer treated with doxorubicin, dexrazoxane is cardioprotective for at least 5 years. However, longer-term data are lacking.
METHODS
Within the Children's Oncology Group and the Dana Farber Cancer Institute's Childhood Acute Lymphoblastic Leukemia Consortium, we evaluated four randomized trials of children with acute lymphoblastic leukemia or Hodgkin lymphoma, who received doxorubicin with or without dexrazoxane, and a nonrandomized trial of patients with osteosarcoma who all received doxorubicin with dexrazoxane. Cumulative doxorubicin doses ranged from 100 to 600 mg/m across these five trials, and dexrazoxane was administered uniformly (10:1 mg/m ratio) as an intravenous bolus before doxorubicin. Cardiac function was prospectively assessed in survivors from these trials, plus a matched group of survivors of osteosarcoma treated with doxorubicin without dexrazoxane. Two-dimensional echocardiograms and blood biomarkers were analyzed centrally in blinded fashion. Multivariate analyses adjusted for demographic characteristics, cumulative doxorubicin dose, and chest radiotherapy determined the differences and associations by dexrazoxane status.
RESULTS
From 49 participating institutions, 195 participants were assessed at 18.1 ± 2.7 years since cancer diagnosis (51% dexrazoxane-exposed; cumulative doxorubicin dose 297 ± 91 mg/m). Dexrazoxane administration was associated with superior left ventricular fractional shortening (absolute difference, +1.4% [95% CI, 0.3 to 2.5]) and ejection fraction (absolute difference, +1.6% [95% CI, 0.0 to 3.2]), and lower myocardial stress per B-type natriuretic peptide (-6.7 pg/mL [95% CI, -10.6 to -2.8]). Dexrazoxane was associated with a reduced risk of having lower left ventricular function (fractional shortening < 30% or ejection fraction < 50%; odds ratio, 0.24 [95% CI, 0.07 to 0.81]). This protective association was primarily seen in those treated with cumulative doxorubicin doses ≥ 250 mg/m.
CONCLUSION
Among young adult-aged survivors of childhood cancer, dexrazoxane was associated with a cardioprotective effect nearly 20 years after initial anthracycline exposure.
Topics: Young Adult; Child; Humans; Aged; Dexrazoxane; Cancer Survivors; Doxorubicin; Antibiotics, Antineoplastic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Osteosarcoma; Bone Neoplasms
PubMed: 36669148
DOI: 10.1200/JCO.22.02423 -
Nutrients Jan 2023Iron functions as an essential micronutrient and participates in normal physiological and biochemical processes in the cardiovascular system. Ferroptosis is a novel type... (Review)
Review
Iron functions as an essential micronutrient and participates in normal physiological and biochemical processes in the cardiovascular system. Ferroptosis is a novel type of iron-dependent cell death driven by iron accumulation and lipid peroxidation, characterized by depletion of glutathione and suppression of glutathione peroxidase 4 (GPX4). Dysregulation of iron metabolism and ferroptosis have been implicated in the occurrence and development of cardiovascular diseases (CVDs), including hypertension, atherosclerosis, pulmonary hypertension, myocardial ischemia/reperfusion injury, cardiomyopathy, and heart failure. Iron chelators deferoxamine and dexrazoxane, and lipophilic antioxidants ferrostatin-1 and liproxstatin-1 have been revealed to abolish ferroptosis and suppress lipid peroxidation in atherosclerosis, cardiomyopathy, hypertension, and other CVDs. Notably, inhibition of ferroptosis by ferrostatin-1 has been demonstrated to alleviate cardiac impairments, fibrosis and pathological remodeling during hypertension by potentiating GPX4 signaling. Administration of deferoxamine improved myocardial ischemia/reperfusion injury by inhibiting lipid peroxidation. Several novel small molecules may be effective in the treatment of ferroptosis-mediated CVDs. In this article, we summarize the regulatory roles and underlying mechanisms of iron metabolism dysregulation and ferroptosis in the occurrence and development of CVDs. Targeting iron metabolism and ferroptosis are potential therapeutic strategies in the prevention and treatment of hypertension and other CVDs.
Topics: Humans; Ferroptosis; Cardiovascular Diseases; Myocardial Reperfusion Injury; Deferoxamine; Lipid Peroxidation; Iron; Hypertension
PubMed: 36771298
DOI: 10.3390/nu15030591 -
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 -
The Cochrane Database of Systematic... Sep 2022This review is the third update of a previously published Cochrane Review. The original review, looking at all possible cardioprotective agents, was split and this part... (Review)
Review
BACKGROUND
This review is the third update of a previously published Cochrane Review. The original review, looking at all possible cardioprotective agents, was split and this part now focuses on dexrazoxane only. Anthracyclines are effective chemotherapeutic agents in the treatment of numerous malignancies. Unfortunately, their use is limited by a dose-dependent cardiotoxicity. In an effort to prevent or reduce this cardiotoxicity, different cardioprotective agents have been studied, including dexrazoxane.
OBJECTIVES
To assess the efficacy of dexrazoxane to prevent or reduce cardiotoxicity and determine possible effects of dexrazoxane on antitumour efficacy, quality of life and toxicities other than cardiac damage in adults and children with cancer receiving anthracyclines when compared to placebo or no additional treatment.
SEARCH METHODS
We searched CENTRAL, MEDLINE and Embase to May 2021. We also handsearched reference lists, the proceedings of relevant conferences and ongoing trials registers.
SELECTION CRITERIA
Randomised controlled trials (RCTs) in which dexrazoxane was compared to no additional therapy or placebo in adults and children with cancer receiving anthracyclines.
DATA COLLECTION AND ANALYSIS
Two review authors independently performed study selection, data extraction, risk of bias and GRADE assessment of included studies. We analysed results in adults and children separately. We performed analyses according to the Cochrane Handbook for Systematic Reviews of Interventions.
MAIN RESULTS
For this update, we identified 548 unique records. We included three additional RCTs: two paediatric and one adult. Therefore, we included a total of 13 eligible RCTs (five paediatric and eight adult). The studies enrolled 1252 children with leukaemia, lymphoma or a solid tumour and 1269 participants, who were mostly diagnosed with breast cancer. In adults, moderate-quality evidence showed that there was less clinical heart failure with the use of dexrazoxane (risk ratio (RR) 0.22, 95% confidence interval (CI) 0.11 to 0.43; 7 studies, 1221 adults). In children, we identified no difference in clinical heart failure risk between treatment groups (RR 0.20, 95% CI 0.01 to 4.19; 3 studies, 885 children; low-quality evidence). In three paediatric studies assessing cardiomyopathy/heart failure as the primary cause of death, none of the children had this outcome (1008 children, low-quality evidence). In the adult studies, different definitions for subclinical myocardial dysfunction and clinical heart failure combined were used, but pooled analyses were possible: there was a benefit in favour of the use of dexrazoxane (RR 0.37, 95% CI 0.24 to 0.56; 3 studies, 417 adults and RR 0.46, 95% CI 0.33 to 0.66; 2 studies, 534 adults, respectively, moderate-quality evidence). In the paediatric studies, definitions of subclinical myocardial dysfunction and clinical heart failure combined were incomparable, making pooling impossible. One paediatric study showed a benefit in favour of dexrazoxane (RR 0.33, 95% CI 0.13 to 0.85; 33 children; low-quality evidence), whereas another study showed no difference between treatment groups (Fischer exact P = 0.12; 537 children; very low-quality evidence). Overall survival (OS) was reported in adults and overall mortality in children. The meta-analyses of both outcomes showed no difference between treatment groups (hazard ratio (HR) 1.04, 95% 0.88 to 1.23; 4 studies; moderate-quality evidence; and HR 1.01, 95% CI 0.72 to 1.42; 3 studies, 1008 children; low-quality evidence, respectively). Progression-free survival (PFS) was only reported in adults. We subdivided PFS into three analyses based on the comparability of definitions, and identified a longer PFS in favour of dexrazoxane in one study (HR 0.62, 95% CI 0.43 to 0.90; 164 adults; low-quality evidence). There was no difference between treatment groups in the other two analyses (HR 0.95, 95% CI 0.64 to 1.40; 1 study; low-quality evidence; and HR 1.18, 95% CI 0.97 to 1.43; 2 studies; moderate-quality evidence, respectively). In adults, there was no difference in tumour response rate between treatment groups (RR 0.91, 95% CI 0.79 to 1.04; 6 studies, 956 adults; moderate-quality evidence). We subdivided tumour response rate in children into two analyses based on the comparability of definitions, and identified no difference between treatment groups (RR 1.01, 95% CI 0.95 to 1.07; 1 study, 206 children; very low-quality evidence; and RR 0.92, 95% CI 0.84 to 1.01; 1 study, 200 children; low-quality evidence, respectively). The occurrence of secondary malignant neoplasms (SMN) was only assessed in children. The available and worst-case analyses were identical and showed a difference in favour of the control group (RR 3.08, 95% CI 1.13 to 8.38; 3 studies, 1015 children; low-quality evidence). In the best-case analysis, the direction of effect was the same, but there was no difference between treatment groups (RR 2.51, 95% CI 0.96 to 6.53; 4 studies, 1220 children; low-quality evidence). For other adverse effects, results also varied. None of the studies evaluated quality of life. If not reported, the number of participants for an analysis was unclear.
AUTHORS' CONCLUSIONS
Our meta-analyses showed the efficacy of dexrazoxane in preventing or reducing cardiotoxicity in adults treated with anthracyclines. In children, there was a difference between treatment groups for one cardiac outcome (i.e. for one of the definitions used for clinical heart failure and subclinical myocardial dysfunction combined) in favour of dexrazoxane. In adults, no evidence of a negative effect on tumour response rate, OS and PFS was identified; and in children, no evidence of a negative effect on tumour response rate and overall mortality was identified. The results for adverse effects varied. In children, dexrazoxane may be associated with a higher risk of SMN; in adults this was not addressed. In adults, the quality of the evidence ranged between moderate and low; in children, it ranged between low and very low. Before definitive conclusions on the use of dexrazoxane can be made, especially in children, more high-quality research is needed. We conclude that if the risk of cardiac damage is expected to be high, it might be justified to use dexrazoxane in children and adults with cancer who are treated with anthracyclines. However, clinicians and patients should weigh the cardioprotective effect of dexrazoxane against the possible risk of adverse effects, including SMN, for each individual. For children, the International Late Effects of Childhood Cancer Guideline Harmonization Group has developed a clinical practice guideline.
Topics: Adult; Anthracyclines; Antibiotics, Antineoplastic; Cardiotonic Agents; Cardiotoxicity; Child; Dexrazoxane; Heart Failure; Humans; Leukemia, Myeloid, Acute; Polyketides; Systematic Reviews as Topic
PubMed: 36162822
DOI: 10.1002/14651858.CD014638.pub2