None of the genotypes associated with an increased risk of doxorubicininduced cardiotoxicity were identified in these two patients. Cardiac function should be assessed at baseline and continue during treatment. The mechanism, clinical manifestations, monitoring, and diagnosis of anthracycline induced cardiotoxicity and cardiovascular complications of other classes of chemotherapy agents are discussed separately. Furthermore, cardiomyocytespecific deletion of top2b protects mice from the development of doxorubicininduced progressive heart failure, suggesting that doxorubicininduced cardiotoxicity is. The protective effect of grape seed extract on cardiotoxicity. In humans, dox cardiotoxicity manifests over two time scales. Reversible doxorubicininduced congestive heart failure. This study investigated the potential cardioprotective effects of rsvl against dox induced cardiotoxicity. However, cumulative dose dependent cardiotoxicity has been a major hurdle where doxorubicin is the primary choice as an antitumor drug.
Doxorubicin, nanoparticles, liposomal, polymeric, protein, gold, cardiotoxicity, nanocarriers. Doxorubicin dox, an anthracycline antibiotic, has a wide spectrum of antitumor activity with doselimiting cardiotoxicity. Adriamycin induced cardiotoxicity mostly develops during the course of therapy up to two months from its termination but late events several months to years after treatment termination have occurred. Doxorubicininduced cardiomyopathy and congestive heart failure were reported in the 1970s. Arthur lebowitz, md \sb\doxorubicin hydrochloride is a chemotherapeutic agent highly effective against a wide range of neoplasms. Both agents began to be incorporated into treatment protocols approximately 40 years ago. Doxorubicin induces cardiotoxicity through upregulation of death. It also showed a higher therapeutic index, yet the cardiotoxicity remained. Our previous study found that rosmarinic acid ra could attenuate pressure overloadinduced cardiac dysfunction via cardiac fibroblasts cfs, however its effect in doxinduced cardiotoxicity remains unknown. In the present study, doxorubicininduced acute cardiotoxicity was prevented in the presence of the antioxidant compound h2545 and its metabolite in langendorff heart perfusion system.
Dox exposure to endothelial cells and cardiomyocytes caused apoptotic cell. Diazoxide protects against doxorubicininduced cardiotoxicity. Ironing out doxorubicinrelated cardiotoxicity blood. Download acrobat pdf file 3mb transparency document. 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. Diverging effects of enalapril or eplerenone in primary. Prevention of doxorubicininduced cardiotoxicity by pharmacological nonhypoxic myocardial preconditioning based on docosahexaenoic acid dha and carvedilol direct antioxidant effects. Doxorubicin as anticancer agent can cause dosedependent cardiotoxicity and heart failure in the long term. Arthur lebowitz, md \sb\ doxorubicin hydrochloride is a chemotherapeutic agent highly effective against a wide range of neoplasms. Pdf reversal of doxorubicininduced cardiotoxicity by. Doxorubicin showed better activity than daunorubicin against mouse tumors, and especially solid tumors. Finally, hearts from patients with doxorubicininduced cardiomyopathy had markedly higher mitochondrial iron levels than hearts from patients with other types of cardiomyopathies or normal. Sexspecific cardiolipin remodelling after doxorubicin treatment.
Our previous study reported that survivin has an antiapoptotic effect against doxorubicin doxinduced cardiotoxicity. Prevention of anthracycline induced cardiotoxicity challenges and opportunities pimprapa vejpongsa, md, edward t. Mechanism of doxorubicin cardiotoxicity evaluated by. Our previous study found that rosmarinic acid ra could attenuate pressure overload induced cardiac dysfunction via cardiac fibroblasts cfs, however its effect in dox induced cardiotoxicity remains unknown. Rutin attenuates doxorubicininduced cardiotoxicity via. May 27, 2014 chemotherapy with doxorubicin is limited by cardiotoxicity. From mechanisms to development of efficient therapy. Prevention of doxorubicininduced acute cardiotoxicity by an.
Kalyanaraman b1, joseph j, kalivendi s, wang s, konorev e, kotamraju s. Rutin as a polyphenolic flavonoid has been illustrated to protect hearts from diverse cardiovascular diseases. Vaidya, sihem aitoudhia center for pharmacometrics and systems pharmacology, department of pharmaceutics, college of. Bonanno1, baikuntha aryal1, francesca mascia1, delaram moshkelani2, steven mog3 and v. A prime limitingfactor to the administration of this drugis cardiotoxicity, which frequently develops when the cumulative dose exceeds 500 mgsq m.
Jci cardiotoxicity of doxorubicin is mediated through. Reversible doxorubicininduced congestiveheart failure murraycohen,md. Doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients. The use of melatonin can lead to a decrease in the cardiotoxic effect induced by doxorubicin. Acute effects occur within 48 h of infusion and are generally reversible and clinically manageable takemura and fujiwara, 2007. Burridge pw, li yf, matsa e, wu h, ong sg, sharma a. Thomas hospital, westminster bridge road, london se1 7eh, uk. Human induced pluripotent stem cellderived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicininduced cardiotoxicity. Highlights the pathogenesis of doxorubicin induced cardiotoxicity is complex and multifactorial. Doxorubicin dox is a cytostatic antibiotic from the class of anthracyclines widely used in chemotherapeutic cancer treatments. It is often used together with other chemotherapy agents. Furthermore, cardiomyocytespecific deletion of top2b protects mice from the development of doxorubicin induced progressive heart failure, suggesting that doxorubicin induced cardiotoxicity is. The manifestations are usually chest pain due to myopericarditis andor palpitations due to sinus tachycardia, paroxysmal nonsustained supraventricular tachycardia and premature.
The authors confirm that this article content has no conflict of interest. Doxorubicininduced cardiotoxicity is suppressed by estrousstaged treatment and exogenous 17. Research paper mechanism of doxorubicin cardiotoxicity evaluated by integrating multiple molecular effects into a biophysical model correspondencedrstevena. Subsequent research has led to many other anthracycline. Frontiers cardiotoxicity of anticancer therapeutics. Dexrazoxane, a drug that attenuates doxorubicininduced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicininduced cardiac damage. Levosimendan prevents doxorubicininduced cardiotoxicity. Cardiomyocyte apoptosis is a key event in the process of doxorubicin doxinduced cardiotoxicity. Doxorubicininduced cardiotoxicity is suppressed by. This includes breast cancer, bladder cancer, kaposis sarcoma, lymphoma, and acute lymphocytic leukemia.
Doxorubicin cardiotoxicity is associated with the generation of free radicals, and involves not only lipid peroxidation but also a. 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. Studies have focused on the effects of leucine supplementation as a strategy to minimize or. Studies have suggested that the mechanism of doxorubicin induced cardiotoxicity involve the formation of free oxygen radicals, expression of nitric. During the 6month followup period there were no patient deaths or interrupted chemotherapy treatments due to doxorubicininduced cardiotoxicity. The drugs toxicity is known to be closely related to the generation of. Taken together, our results suggest that levosimendan, exerted cardioprotection against acute doxorubicininduced cardiotoxicity, mainly by restoring the oxidative status of the doxorubicintreated myocardium. Doxorubicin induced cardiotoxicity is dose dependent and controlled monitoring of dose is the best possible way to prevent toxicity.
Delayed cardiomyopathy is manifested by reduced left ventricular ejection fraction lvef andor signs and symptoms of. Pdf doxorubicininduced cardiotoxicity researchgate. Doxorubicininduced cardiotoxicity is suppressed by estrous. Interventions to reduce the cardiotoxicity of doxorubicin are clinically relevant. We then update the findings of molecular biology of doxinduced cardiomyopathy including molecular mechanisms, established and putative. 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. Nebivolol effect on doxorubicininduced cardiotoxicity in. Congestive heart failure in patients treated with doxorubicin a retrospective analysis of three trials sandra m. However, clinical use of this drug is hampered by its cardiotoxicity, which is manifested as. Prevention of doxorubicininduced acute cardiotoxicity by. The lifethreatening toxic side effects are related to cardiotoxicity heart failure, cardiomyopathy that occurs many years after the cessation of cancer treatment and. Doxorubicin induced apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic effects, toxicities, or both. Free radical generation and mitochondrial dysfunction are thought to contribute to doxorubicin induced cardiac failure.
Unexpected doxorubicininduced cardiomyopathy in sisters pdf. Apr 18, 2017 thus, the aim of the present study was to evaluate the impact of mr antagonist treatment on doxorubicin induced cardiotoxicity and to identify the role of cardiac myocyte mr using celltype specific gene targeting in a mouse model. Doxorubicin is a widely used chemotherapy drug, but its application is associated with cardiotoxicity. Pharmacological preconditioning mimicking ischemic preconditioning has been demonstrated with morphine and represents an acceptable clinical intervention. Background doxorubicin, a commonly used anticancer drug, is known to cause serious and potentially lifethreatening cardiotoxicity. However, its clinical success is limited because it increases hematotoxicity in cancer patients 14,15.
Doxorubicininduced apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic effects, toxicities, or both. Bone marrow is a source of regenerated cardiomyocytes in doxorubicin induced cardiomyopathy and granulocyte colonystimulating factor enhances migration of bone marrow cells and attenuates cardiotoxicity of doxorubicin under electron microscopy. Recently, swain et al 1 reported that doxrelated cardiotoxicity and induced congestive heart failure occur at a greater frequency than was previously reported, and that patients of advanced age may be at a greater risk. Mar 16, 2017 doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients. Curcumin attenuates doxorubicininduced cardiotoxicity by. Molecular mechanisms, preventive strategies, and early monitoring nadine wenningmann, merle knapp, anusha ande, tanaya r. A prime limitingfactor to the administration of this drugis cardiotoxicity, which frequently develops when the cumulative. We evaluated the myocardial damage in rats treated with doxorubicin dox. Yeh, mdy abstract anthracycline compounds are major culprits in chemotherapyinduced cardiotoxicity, which is the chief limiting factor in delivering optimal chemotherapy to cancer patients.
Doxorubicin induced cardiomyopathy and congestive heart failure were reported in the 1970s. Doxorubicin and daunorubicin together can be thought of as prototype compounds for the anthracyclines. Prevention of doxorubicin induced cardiotoxicity by pharmacological nonhypoxic myocardial preconditioning based on docosahexaenoic acid dha and carvedilol direct antioxidant effects. Thus, elevation of akt signaling and inhibition of autophagy and apoptosis in the heart provide the new strategies for treatment of doxinduced cardiotoxicity. Aggressive management of doxorubicininduced cardiomyopathy associated with low doses of doxorubicin. Doxorubicin induces cardiotoxicity in a pluripotent stem. The mechanism, clinical manifestations, monitoring, and diagnosis of anthracyclineinduced cardiotoxicity and cardiovascular complications of other classes of chemotherapy agents are discussed separately. Congestive heart failure in patients treated with doxorubicin. Risk factors for developing doxorubicin induced cardiotoxicity include. Doxorubicinassociated mitochondrial iron accumulation. Nowadays echocardiography is used to monitor doxorubicininduced and this is cardiotoxicity considered as gold standard test 14. Full text is available as a scanned copy of the original print version. Cardiotoxicity is a wellrecognized side effect of anthracycline therapy that limits the total amount of drug administered and can cause heart failure. New signal transduction paradigms in anthracyclineinduced.
Doxorubicin has been used extensively for the treatment of hematological cancers, cancers of breast, lung and bone, and soft tissue sarcomas. Get a printable copy pdf file of the complete article 242k, or click on a page image below to browse page by page. Effect of carvedilol on silent anthracyclineinduced. The hypothesis that doxorubicin mediated cardiomyopathy is mediated by top2beta in cardiomyocytes is supported by murine studies showing that cardiomyocytespecific deletion of the gene top2b which encodes the top2beta enzyme protects cardiomyocytes from doxorubicin induced dna doublestrand breaks and transcriptome changes that are. Links to pubmed are also available for selected references. By danubia silva dos santos and regina coeli dos santos. One of the most prominently used and readily identifiable is the anthracycline dox. Cardioprotective effects of statin in doxorubicininduced. Nebivolol effect on doxorubicininduced cardiotoxicity in breast cancer flavia cochera, daniel dinca, diana aurora bordejevic, ioana mihaela citu, adelina marioara mavrea, minodora andor, mihai trofenciuc, mirela cleopatra tomescu cardiology department, victor babes university of medicine and pharmacy, timisoara, romania these authors contributed equally to this work purpose. Nox2 nadph oxidase promotes pathologic cardiac remodeling associated with doxorubicin chemotherapy. Despite the efficiency against several types of cancer, the use of dox remains limited due to the side effects, especially cardiotoxicity. Dexrazoxane, a drug that attenuates doxorubicininduced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicininduced.
Doxorubicin, sold under the brand name adriamycin among others, is a chemotherapy medication used to treat cancer. Prevention of doxorubicininduced cardiotoxicity by. Anthracyclines, a class of chemotherapy drugs, are traditional cancer therapies that have been effective in treating many forms of cancer for the last half century. Doxorubicin has remarkable antineoplastic effect, which establishes its potential for use against a variety of tumors in the clinical practice. As we previously showed, a decrease in cl content particularly in doxotreated males, analysis of cardiolipin species was necessary to dissect this deficit. Reduction of doxorubicininduced cardiotoxicity using nanocarriers. It is becoming increasingly clear that apoptosis of myocardial cells plays a critical role in the onset of cardiomyopathy. Get a printable copy pdf file of the complete article. Tunelpositive cells were imaged under a fluorescence 228 mic roscope at excitation and emission wavele ngths of 488 and 530 nm, respectively. However, doxorubicin induced cardiotoxicity is considered as a serious adverse effect, and it limits the clinical use of this chemotherapeutic drug.
Even though the evidence for myocardial damage induced by ros is vast, oxidative stress as the sole cause of cardiotoxicity is increasingly questioned and more research is dedicated to alternative pathways. The incidence of acute cardiotoxicity is approximately 11% 3,4. It is widely utilized in the therapy of variety of haematological and solid tumours, although its. Myocardial damage, including acute left ventricular failure, can occur with doxorubicin hydrochloride. Numerous studies have focused on the mechanism of anthracycline cardiotoxicity. Doxorubicin cardiotoxicity is thought to be mediated through freeradical injury. Studies have suggested that the mechanism of doxorubicininduced cardiotoxicity involve the formation of free oxygen radicals, expression of nitric. The occurrence of heart failure with ventricular dysfunction may lead to severe cardiomyopathy and ultimately to death. Doxorubicin as a chemotherapeutic drug is widely used for the treatment of patients with cancer.
Liposomal doxorubicin and pegylated liposomal doxorubicin demonstrated favorable toxicity profiles with better cardiac safety and less myelosuppression, alopecia, nausea and vomiting compared with the conventional anthracyclines. 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. Doxorubicininduced cardiotoxicity and cardioprotective. Prevention of anthracyclineinduced cardiotoxicity challenges and opportunities pimprapa vejpongsa, md, edward t. Tomita s, ishida m, nakatani t, fukuhara s, hisashi y, ohtsu y, et al. Molecular mechanisms of doxorubicininduced cardiotoxicity. Comparison of safety and toxicity of liposomal doxorubicin.
Derivation of anthracycline and anthraquinone equivalence. Doxorubicin is given by injection into a vein common side effects include hair loss, bone. The mechanisms of doxorubicin induced cardiotoxicity remain incompletely understood. The hypothesis that doxorubicinmediated cardiomyopathy is mediated by top2beta in cardiomyocytes is supported by murine studies showing that cardiomyocytespecific deletion of the gene top2b which encodes the top2beta enzyme protects cardiomyocytes from doxorubicininduced dna doublestrand breaks and transcriptome changes that are. Dox induced cardiotoxicity is classified as type i, or irreversible. Cells treated with doxorubicin have been shown to manifest the characteristic morphologic changes associated with apoptosis or programmed cell death. Original article alleviation of doxorubicininduced. Dose reduction protocols have been proposed to avoid the risk of delayed cardiotoxicity, but this might be at the expense of the.
This article is from turkish journal of hematology, volume 31. Doxorubicin induces cardiotoxicity through upregulation of. The iron chelator icrf187 has been shown to protect against dox induced cardiotoxicity. Luteolin attenuates doxorubicininduced cardiotoxicity. Randomized controlled trials were sought using comprehensive searches of electronic databases in june 2008. New signal transduction paradigms in anthracyclineinduced cardiotoxicity. The mechanisms of doxorubicininduced cardiotoxicity remain incompletely understood. Doxorubicin is a highly efficacious anticancer drug but causes cardiotoxicity in many patients.
Potentiation of doxorubicin cardiotoxicity by iron loading in. The present study investigated whether the practice of exercise has a protective effect against cardiac toxicity induced by doxorubicin dox. Advances in bioscience and biotechnology, 5, 10781089. Inhibition of the cardiac myocyte mineralocorticoid receptor. In the present study, doxorubicin induced acute cardiotoxicity was prevented in the presence of the antioxidant compound h2545 and its metabolite in langendorff heart perfusion system.
The mechanisms of doxorubicin induced cardiotoxicity dic remain incompletely understood. Download acrobat pdf file 8mb transparency document. Doxorubicin dox is the predominant anthracycline, but its use is limited due to cardiotoxicity octavia et al. Unexpected doxorubicininduced cardiomyopathy in sisters. Doxorubicin is a widely used as a component of chemotherapy regimes. Doxorubicininduced heart failure can appear very late after the last administration. The incidence of ppe was similar in both arms or 1. Doxorubicin induced heart failure can appear very late after the last administration. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a. Free fulltext pdf articles from hundreds of disciplines, all in one place. Beautiful piano music 247 study music, relaxing music, sleep music, meditation music soothing relaxation 4,446 watching live now. Objectives the role of iron toward doxorubicin dox cardiotoxicity was studied using a rodent model of dietary carbonyl iron loading. Doxorubicin induces cytotoxicity through upregulation of.
Pdf morphine enhances doxorubicininduced cardiotoxicity. Adriamycin therapy is also contraindicated in patients with marked liver impairment, in pregnancy and lactation see precautions, in the presence of generalised infection, and in patients with hypersensitivity to adriamycin andor other anthracyclines or anthracenediones. Dox exposure to endothelial cells and cardiomyocytes caused apoptotic cell death at submicromolar. Michaela fojtu, jaromir gumulec, tibor stracina, martina raudenska, anna skotakova, marketa vaculovicova, vojtech adam, petr babula, marie novakova and michal masarik affiliation.
The her2 inhibitor lapatinib potentiates doxorubicin. Anthracycline antibiotic doxorubicin dox is a very potent and extensively prescribed chemotherapeutic drug. Aggressive management of doxorubicin induced cardiomyopathy associated with low doses of doxorubicin. Frontiers increased dietary leucine reduces doxorubicin. Curcumin attenuates doxorubicin induced cardiotoxicity by.
There is no specific curative or preventive treatment available. Highlights the pathogenesis of doxorubicininduced cardiotoxicity is complex and multifactorial. Oxidative stress is a major cause of doxorubicin induced cardiotoxicity. Statin use was associated with a lower risk for incident heart failure in breast cancer patients with dox chemotherapy. Doxorubicin is a valuable antineoplastic drug although its clinical use is greatly hindered by its severe cardiotoxicity with dismal target therapy available. Luteolin is a natural product extracted from vegetables and fruits with a wide range of biological efficacies including antioxidative, antitumorigenic, and antiinflammatory properties. Pdf on nov 14, 2018, danubia silva dos santos and others published doxorubicininduced cardiotoxicity.
Because of the four acyl chains, a great variety of cl was identified additional file 1. Free radical generation and mitochondrial dysfunction are thought to contribute to doxorubicininduced cardiac failure 1, 2. Teaching the basics of the mechanism of doxorubicininduced. The first indication that doxorubicininduced cardiotoxicity is not solely due to redox cycling of doxorubicin comes from the pioneering work of zhang et al. We next focused on the effects of a repeated versus single treatment dose of levosimendan in subchronic doxorubicininduced cardiotoxicity.
In conclusion, a number of natural products have been shown with protective actions against doxorubicininduced cardiotoxicity, and some exhibit a potential therapeutic value for clinical applications. Department of physiology, faculty of medicine, masaryk university. Oxidative stress is a major cause of doxorubicininduced cardiotoxicity. Hemodynamic monitoring in shock and implications for management.
Dexrazoxane, a drug that attenuates doxorubicin induced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicin induced cardiac damage. Doxorubicin cardiotoxicity can be acute, occurring during and within 23 days of its administration. Rosmarinic acid alleviates cardiomyocyte apoptosis via. This study aimed at identifying the pathophysiological mechanisms by which mineralocorticoid receptor antagonism mra or angiotensin converting enzyme inhibition acei provide protection against doxorubicin induced cardiotoxicity dic in mouse models of acute and chronic toxicity.
Cardiomyocyte apoptosis is a key event in the process of doxorubicin dox induced cardiotoxicity. The molecule is amphoteric, containing acidic 66 functions in the ring phenolic groups and a basic function in the sugar amino group. As iron accumulation increases with age, this observation has profound implications when considered along with the results presented by. Modeling doxorubicininduced cardiotoxicity in human. Doxorubicin hydrochloride for injection, usp 3 doxorubicin. Doxorubicin pi may 8, 2003 3 65 sugar, producing a hydrophilic center. Bone marrow is a source of regenerated cardiomyocytes in doxorubicininduced cardiomyopathy and granulocyte colonystimulating factor enhances migration of bone marrow cells and attenuates cardiotoxicity of doxorubicin under electron microscopy. Reduction of doxorubicininduced cardiotoxicity using. Reversible doxorubicin induced congestiveheart failure murraycohen,md.