Left ventricular ejection fraction assessments at both baseline and end of study. Jci cardiotoxicity of doxorubicin is mediated through. Doxorubicin induced cardiomyopathy typically results in dilated cardiomyopathy, with all four cardiac chambers being enlarged. By danubia silva dos santos and regina coeli dos santos.
Mechanism of doxorubicin cardiotoxicity evaluated by. Mar 16, 2017 doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients. The mechanisms of doxorubicin induced cardiotoxicity remain incompletely understood. It is usually evident within 30 days of administration of its last dose, but it may occur even after 610 years after its administration.
Anthracycline therapy is associated with an increase in the risk for developing heart failure with significant associated morbidity and mortality 1. Although cardiomyocyte has been considered a classical cellular target, other cells including various types of. Anthracyclines doxorubicin, daunorubicin, epirubicin and idarubicin are used in a wide range of cancers including breast and lymphoma. The cardiotoxicity of doxorubicin is becoming an interdisciplinary point of interest given a growing population of cancer survivors.
This toxicity has previously led to the postmarketing withdrawal of numerous pharmacologically active drugs and limits the efficacy of other clinically useful ones. Although the mechanism of doxinduced cardiotoxicity is still not. The aim of this study was to determine the protective effect of vitamin e and telmisartan in acute doxorubicin induced cardiotoxicity. Finally, hearts from patients with doxorubicin induced. In addition to dox induced cardiotoxicity, it also causes hepatotoxicity address for.
Attenuation of doxorubicininduced cardiotoxicity by mdivi1. Quercetin attenuating doxorubicin induced hepatic, cardiac. The chemical name of doxorubicin hydrochloride is 8s,10s103amino2,3,6trideoxy. Prevention of anthracycline induced cardiotoxicity challenges and opportunities pimprapa vejpongsa, md, edward t. Fortysix patients with recurrent metastatic breast cancer were treated with a combination chemotherapy including doxorubicin and mitomycin c. Springer nature molecular and cellular biochemistry doxorubicin induced apoptosis. Doxorubicin, an anthracycline antibiotic commonly used as a chemotherapeutic agent for breast cancer, is well known to cause cardiotoxicity.
Doxorubicin dox, an anthracycline antibiotic, is a kind of chemotherapeutical agent widely used in solid tumors 1, 2. Cardiac function should be assessed at baseline and continue during treatment. Doxorubicin is a powerful anthracycline antibiotic used to treat a multitude of human neoplasms. Original article silymarin decreases the expression of. Molecular mechanisms, preventive strategies, and early monitoring nadine wenningmann, merle knapp, anusha ande, tanaya r.
The clinical features of the studied patients are listed in table 1. In the case of liposomal doxorubicin, cardiotoxicity is reduced significantly. Doxorubicin dox induces oxidative stress leading to cardiotoxicity. The mechanisms of ant cardiotoxicity have been the subject of considerable controversy, and dozens of various potential pathways have been proposed and studied 1, 7, 17, 35, 53, 59, 93, 95, 110, 120, 140. Doxorubicin induces cardiotoxicity in a pluripotent stem. Yeh, mdy abstract anthracycline compounds are major culprits in chemotherapy induced cardiotoxicity. Doxorubicin, nanoparticles, liposomal, polymeric, protein, gold, cardiotoxicity, nanocarriers. This study examined the gender differences in doxorubicin induced apoptosis. For language access assistance, contact the ncats public information officer. In support of this model, an inhibition of mrp2 expression by a bacterial toxin decreased biliary clearance of doxorubicin and increased its plasma concentration. Reduction of doxorubicininduced cardiotoxicity using. There are several risk factors for cardiotoxicity induced by anthracyclines, such as total cumulative dose, additional treatment, existing cardiomyopathy, age, and sex. However, its usage is limited by cardiotoxicity, which is related to the cumulative. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation.
However, doxorubicin causes severe cardiac toxicity, which compromises its clinical usefulness. Nadph oxidase and multidrug resistance protein genetic. Anthracycline antibiotic doxorubicin dox is a very potent and extensively prescribed chemotherapeutic drug. Means of evaluation and protection from doxorubicininduced cardiotoxicity and hepatotoxicity in rats article pdf available in journal of cancer research and therapeutics 102. June 29 issue1 has confirmed the results of an earlier study of 150 survivors of cancer who were treated at the childrens hospital of philadelphia. The role of autophagy rita zilinyi 1, attila czompa 1, andras czegledi 1, andrea gajtko 2, dora pituk 1. Doxorubicininduced cardiomyopathy 17 years after chemotherapy. During therapy there was a progressive deterioration of myocardial function, and this phenomenon was found to be linearly correlated to the cumulative dose of doxorubicin. Doxorubicin is a potent anthracycline antineoplastic drug used to treat a wide range of malignancies1. Pdf effect of melatonin on the cardiotoxicity of doxorubicin. Possible enhancement of the cardiotoxicity of doxorubicin. Diohf protects against doxorubicininduced cardiotoxicity through. Reprinted by permission from springer nature customer service centre gmbh. Shortly after their introduction, the cardiovascular toxicity has been noticed and reported 25.
Cardiotoxicity, doxorubicin, rnabinding protein quaking, statins. Doxorubicin, also known as adriamycin or rubex, is an anthracycline antibiotic that was discovered from a mutated strain of streptomyces peucetius. Early results of clinical trials suggest that combining trastuzumab or a taxane. Pdf new insights into doxorubicininduced cardiotoxicity. Mitochondriatargeting small molecules effectively prevent. Doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients. Dec 11, 2009 the incidence of chronic doxorubicin cardiotoxicity is much lower, with an estimated incidence of about 1. From bioenergetic failure and cell death to cardiomyopathy.
The incidence of doxorubicin cardiomyopathy is primarily related to its dose. In this study we wanted to investigate if opening of mitochondrial katpchannels by diazoxide is protective against doxorubicin cardiotoxicity, and if 5hydroxydecanoate 5hd, a selective mitochondrial katpchannel. However, various limitations that reduce the therapeutic efficacy are presented in the dox based chemotherapy. The anticancer drug doxorubicin dox also referred to as adriamycin is highly effective in the treatment of a broad range of cancers. Cancer therapies have been shown to induce cardiovascular complications. The aims of this study were to establish an in vitro induced pluripotent stem cell model ipsc of anthracycline induced cardiotoxicity. Risk factors for cardiotoxicity induced by anthracyclines.
Doxorubicin adriamycin and the related anthracycline antibiotic daunorubicin play a central part in cancer therapy because of their efficacy in the treatment of hematologic cancers both acute le. The mechanisms of doxorubicin induced cardiotoxicity dic remain incompletely. Cases were stratified by cumulative dose of doxorubicin. Dox induced cardiac oxidative stress, toxicity, and dysfunction. Doxorubicin dox is the predominant anthracycline, but its use is limited due to cardiotoxicity octavia et al. Effect of desferrioxamine on doxorubicininduced cardiotoxicity and haematotoxicity in mice. In addition to a causative role of oxidative stress, autophagy appears to play an important role in the regulation of dox induced cardiotoxicity. However, its clinical application has been largely limited by potential development of. Role of silymarin against doxorubicin induced cardiotoxicity. Animal studies have shown activity in a spectrum of experimental tumors, immunosuppression, carcinogenic properties in rodents. Here, we demonstrate that inhibiting transient receptor potential canonical 3 trpc3 channels abolishes doxorubicin induced myocardial atrophy in mice.
Considering oxidative stress to be the primary cause of dox induced cardiomyopathy 3, 4, we first determined myocardial oxidative stress and cell death in the acute model of dox induced cardiotoxicity which has been characterized as a rapid cardiomyocyte necrosis and reduced cardiac output within 4 days after a single. Topoisomerase iibeta mediated dna doublestrand breaks. A major green tea component, epigallocatechin3gallate, ameliorates doxorubicinmediated cardiotoxicity in cardiomyocytes of neonatal rats. The anthracycline doxorubicin dox has proved to be one of the most widely used and most effective antitumor drugs since its emergence in the 1960s. May 27, 2014 chemotherapy with doxorubicin is limited by cardiotoxicity. We report the case of an active, otherwise healthy 57yearold. It is widely utilized in the therapy of variety of haematological and solid tumours, although its. Ichikawa y, ghanefar m, bayeva m, wu r, khechaduri a, naga prasad sv, mutharasan rk, naik tj, ardehali h. Risk factors for developing doxorubicin induced cardiotoxicity. Piperine has been reported to suppress inflammatory response and. Doxorubicin induced cardiomyopathy genetic and rare. The fraction of patients who developed posttreatment cardiotoxicity, defined as congestive heart failure or a leftventricular ejection fraction less than 45%, was compared with that from a retrospective study of 399 patients of unknown age and racial distribution.
Teaching the basics of the mechanism of doxorubicin. Yeh, mdy abstract anthracycline compounds are major culprits in chemotherapy induced cardiotoxicity, which is the chief limiting factor in delivering optimal chemotherapy to cancer patients. Anthracycline induced cardiotoxicity aic is a major cause of cancer survivor morbidity and mortality 24, particularly when patients develop heart failure hf 5. Erbb2erbb4 and nrg1 signalling anthracyclines may also disrupt neuregulinerbb nrg re. Pdf means of evaluation and protection from doxorubicin. This results in both systolic and diastolic dysfunction. Previous studies have found that apoptotic cell death is a key component in dox induced cardiotoxicity. The anthracycline doxorubicin dox is widely used in the treatment of. Doxorubicin also induces transcription of endothelial nitric oxide synthase enos and increases the activity of the expressed protein in endothelial cells, 73 and dox is directly reduced at the enos reductase domain, enhancing superoxide formation.
The exact mechanism of the doxinduced cardiotoxicity and its. Vitamin e and telmisartan attenuates doxorubicin induced. Accordingly, we explored a role of nuclear factor erythroid2 related factor 2 nrf2 in dox. Kozluca o, olcay e, surucu s, guran z, kulaksiz t, uskent n. Doxorubicin operates on several levels by different molecular mechanisms including an interaction with iron, upsetting calcium homeostasis, altering the activity of intracellular or intramitochondrial oxidant enzymes, and binding to. Pdf doxorubicininduced cardiotoxicity and cardioprotective. Doxorubicin cardiotoxicity is thought to be mediated through freeradical injury. The effect of monohydroxyethylrutoside on doxorubicininduced. Dox exposure to endothelial cells and cardiomyocytes caused apoptotic cell death at submicromolar. In humans, dox cardiotoxicity manifests over two time scales. Pdf new developments in anthracyclineinduced cardiotoxicity.
Green tea catechinbased complex micelles combined with. Pharmaceutical measures to prevent doxorubicininduced. Objectives the role of iron toward doxorubicin dox cardiotoxicity was studied using a rodent model of dietary carbonyl iron loading. Prevention of doxorubicin induced cardiotoxicity by catechin. Doxorubicin cardiotoxicity is associated with the generation of free radicals, and involves not only lipid peroxidation but also a decreased biosynthesis of highly unsaturated fatty acids, leading. Drug schedule relative university of wisconsinmadison. Free radical generation and mitochondrial dysfunction are thought to contribute to doxorubicin induced cardiac failure. Modeling doxorubicininduced cardiotoxicity in human.
Doxorubicin dox is a potent anthracycline antibiotic drug used to treat a variety of malignancies. Gharanei m, hussain a, janneh o, maddock h 20 attenuation of doxorubicininduced cardiotoxicity by mdivi1. Piperine alleviates doxorubicininduced cardiotoxicity via. Doxorubicin is a highly efficacious anticancer drug but causes cardiotoxicity in many patients. However, the utility of dox is compromised by its potential lethal cardiotoxicity. Potentiation of doxorubicin cardiotoxicity by iron loading in. In this study of the northern california oncology group, myofibrillar loss and sarcoplasmic vacuolization were identified and shown to be identical to those previously described for doxorubicin. Doxorubicin dox, adriamycin is one of the original anthracyclines isolated in the early 1960s from the pigmentproducing bacterium streptomyces peucetius, together with daunorubicin dnr. The cumulative probability of doxorubicin induced cardiotoxicity was estimated. If you have problems viewing pdf files, download the latest version of adobe reader.
Doxorubicin induced apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic effects, toxicities, or both. The mechanism of doxorubicin induce cardiotoxicity is multifactorial includes free. The complex and not completely understood pathogenesis of this complication makes difficult to design successful preventive or curative measures. Pdf doxorubicin dox is a cytostatic antibiotic from the class of anthracyclines widely used in chemotherapeutic cancer treatments. We then update the findings of molecular biology of doxinduced cardiomyopathy including molecular mechanisms, established and putative. Doxorubicin is a highly effective anticancer agent but also induces myocardial atrophy through a largely unknown mechanism.
Pdf doxorubicininduced cardiotoxicity researchgate. Sexual dimorphism of doxorubicinmediated cardiotoxicity. The first step to diminish the incidence of dox cardiotoxicity is to use doses lower than 450 mgm 2, although it is becoming more and more apparent that while lowered cumulative dose. Genetic and rare diseases information center gard po box 8126, gaithersburg, md 208988126 tollfree. Doxorubicin induces cardiotoxicity through upregulation of. Dexrazoxane, a drug that attenuates doxorubicin induced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicin induced cardiac damage. Prevention of doxorubicininduced cardiotoxicity by. However, the clinical use of dox is limited by a significant dosedependent cardiotoxicity, which may lead to endstage heart failure2. Drug induced cardiotoxicity is a major adverse effect that has been encountered for some clinically important drugs especially antineoplastic agents. Myocardial contractility was monitored by means of echocardiography. Doxorubicin liposomal fda prescribing information, side. From mechanisms to development of efficient therapy.
It is becoming increasingly clear that apoptosis of myocardial cells plays a critical role in the onset of cardiomyopathy. Pdf protection against doxorubicininduced cytotoxicity. The anthracyclines and related compounds doxorubicin, daunorubicin, idarubicin, epirubicin, and the anthraquinone mitoxantrone are among the chemotherapeutic agents implicated in cardiotoxicity. Resveratrol attenuates doxorubicininduced cardiomyocyte. Anthracyclineinduced cardiotoxicity and the cardiacsparing effect of liposomal. They combine with bax, a proapoptotic protein, to prevent its oligomerization. Oxidative stress, inflammation and cardiac apoptosis were closely involved in doxorubicin dox induced cardiac injury. It has been shown that free radicals are involved in acute doxorubicin induced toxicity. Females are believed to be better protected against cardiovascular insults. However, as of individual variation, signs of cardiotoxicity have also been seen with cumulative dosages below 300 mgm 2 2,14. Trastuzumab and doxorubicinrelated cardiotoxicity and the.
The doxinduced cardiotoxicity was accompanied by erk12 activation and abolished by the silence of. Since both reperfusion injury and doxorubicininduced cardiotoxicity share similar characteristics, this study aimed to determine whether the risk and safe pathways are activated in response to longterm doxorubicin treatment. Doxorubicin hydrochloride liposome injection is doxorubicin hydrochloride, an anthracycline topoisomerase inhibitor, that is encapsulated in pegylated liposomes for intravenous use. Myricitrin protects against doxorubicininduced cardiotoxicity by. Doxorubicin is an effective anticancer drug with known cardiotoxic. Finally, hearts from patients with doxorubicin induced cardiomyopathy had markedly higher mitochondrial iron levels than hearts from patients with other types of cardiomyopathies or normal. Doxorubicin dox is one of the most effective anticancer drugs to treat various forms of cancers. Trastuzumab and doxorubicin cardiotoxicity one side effect of the treatment of metastatic breast cancer with trastuzumab and dox is the development of a dosedependent cardiotoxicity, characterized by an. Fortytwo evaluable endomyocardial biopsies were obtained from 29 patients treated with epirubicin, the 4epimer of doxorubicin in cumulative doses ranging from 147 mgm2 to 888 mgm2.
The anticancer therapy of doxorubicin dox has been limited by its acute and chronic cardiotoxicity. Identification of the molecular basis of doxorubicin induced cardiotoxicity. As the former strategy might reduce the dox efficacy, combining dox with a. From mechanisms to development of efficient therapy find, read and cite all the.
New insights into doxorubicininduced cardiotoxicity. Acute effects occur within 48 h of infusion and are generally reversible and clinically manageable takemura and fujiwara, 2007. Doxorubicin dox is an effective chemotherapeutic drug in the treatment of various types of cancers. Our study was aimed to find out the protective effect of diosgenin dox induced against cardiotoxicity. Cardiotoxicity refers to deleterious and unwanted side effects of therapeutic compounds on heart function. Llyxohexopyranosyloxy8glycolyl7,8,9,10tetrahydro6,8,11trihydroxy. The importance of doxorubicin dox, as a potent antitumor antibiotic, is limited by the development of lifethreatening cardiomyopathy. A total of 48 patients with diverse sarcoma histologies were evaluated for doxorubicin induced cardiotoxicity and tumor response. Cardiotoxicity cardiotoxicity index compared with doxorubicin given by standard schedulec recommended maximum doseb mgm2 doxorubicin rapid infusion 1 1 1 400 doxorubicin weekly 1 0. The mechanisms of doxorubicin induced cardiotoxicity dic remain incompletely understood.
Diazoxide protects against doxorubicininduced cardiotoxicity. Doxorubicin cardiotoxicity, myocardial homeostasis, progenitor cells background anthracyclines, including doxorubicin dox, discovered nearly a halfcentury ago, are still a backbone of lifesaving chemotherapy schemes 1. In addition, overexpression of gpx1, a cytosolic and mitochondrial enzyme that reduces hydrogen peroxide h2 o 2 and fatty acid hydroperoxides, protects mice hearts against acute doxorubicininduced cardiotoxicity. Pdf doxorubicin is useful anticancer drug because its used in treatment of acute.
Doxorubicin cardiotoxicity, myocardial homeostasis, progenitor cells background anthracyclines, including doxorubicin dox, discovered nearly a halfcentury ago, are still a backbone. Early evidence of cardiotoxicity and tumor response in. Trpc3nox2 complex mediates doxorubicininduced myocardial. Besides this, combining dox with other anticancer drugs. Anthracyclineinduced cardiotoxicity and the cardiacsparing effect. Dioscorea opposita, has been reported to have antioxidant activity. Effect of melatonin on the cardiotoxicity of doxorubicin article pdf available in histology and histopathology 194.
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