From mechanisms to development of efficient therapy find, read and cite all the research. Doxorubicin is a highly effective anticancer agent but also induces myocardial atrophy through a largely unknown mechanism. Heart rate dynamics in doxorubicininduced cardiomyopathy. Early on, it was shown that several enzymes including the cytochrome p450 reductase, nadh dehydrogenase, and xanthine oxidoreductase could reduce dox via a oneelectron reduction mechanism,,,,, giving rise to the semiquinone intermediate that can rapidly reduce oxygen to superoxide o 2 via a futile redox. Apr 18, 2017 in up to 10% of patients acute doxorubicin induced cardiotoxicity occurs within days after doxorubicin administration.
Two mouse models of doxorubicin induced cardiomypathy. Chemotherapyinduced cardiotoxicity is a serious complication that poses a serious threat to life and limits the clinical use of various chemotherapeutic agents, particularly the anthracyclines. Doxorubicininduced chronic cardiotoxicity and its protection. The manifestations are usually chest pain due to myopericarditis andor palpitations due to sinus tachycardia, paroxysmal nonsustained supraventricular tachycardia and premature atrial and ventricular. Lipid emulsion inhibits the late apoptosiscardiotoxicity. Drug induced cardiotoxicity is a major adverse effect that has been encountered for some clinically important drugs especially antineoplastic agents. Here we test timefrequency analysis of heart rate hr variability hrv for early detection of doxorubicininduced cardiotoxicity.
Nadph oxidase and multidrug resistance protein genetic. Detection of chemotherapyinduced cardiotoxicity has historically relied on clinical presentation and cardiac imaging measures. Reversible doxorubicininduced congestive heart failure. Activation of the met receptor attenuates doxorubicin. Arthur lebowitz, md \sb\doxorubicin hydrochloride is a chemotherapeutic agent highly effective against a wide range of neoplasms. Cardiotoxicity is a general term used to define toxicity that affects the heart. Because of the tremendous burden of managing dox induced cardiotoxicity, rapid discovery of effective treatments would be of great. Doxorubicin is given by injection into a vein common side effects include hair loss, bone marrow suppression. Dox is a quinonecontaining anthracycline family of drugs. The mechanism for doxorubicininduced cardiotoxicity is controversial, and numerous hypotheses have been proposed in past decades. Despite the enormous amount of research conducted in this area, the exact molecular mechanisms underlying dox toxic effects on the heart are still an area that warrants further investigations. Pdf doxorubicininduced cardiotoxicity researchgate. Smuder, phd2, and reid hayward, phd3 abstract introduction. Doxorubicininduced chronic cardiotoxicity and its protection by liposomal administration1 aquilur rahman,2 newton more, and philip s.
Spraguedawley rats were divided into four groups at random. Detection of chemotherapy induced cardiotoxicity has historically relied on clinical presentation and cardiac imaging measures. Rats were divided into 4 groups based on their food intake ad libitum. Chemotherapy induced cardiotoxicity is a serious complication that poses a serious threat to life and limits the clinical use of various chemotherapeutic agents, particularly the anthracyclines. The mechanisms of doxorubicininduced cardiotoxicity remain incompletely understood. Melatonin attenuates doxorubicininduced cardiotoxicity through preservation of yap expression hairu li1,2 chao wang1,2 ping sun1,2 dandan liu2,3 guoqing du1,2 jiawei tian1,2 this is an open access article under the terms of the creative commons attribution license, which permits use, distribution and reproduction in any medium. Early detection of doxorubicininduced cardiotoxicity with. Anthracyclines, such as doxorubicin, are among the most valuable treatments for various cancers, but their clinical use is limited due to detrimental side effects such as cardiotoxicity. Protective effect ofspirulina against doxorubicininduced.
While cumulative dose is the greatest risk factor for developing doxorubicin induced cardiotoxicity, several other factors may also contribute to the likelihood of developing heart failure. Effect of desferrioxamine on doxorubicininduced cardiotoxicity and haematotoxicity in mice. Cardiomyocyte death in doxorubicinin duced cardiotoxicity. Doxorubicin dox is one of the most effective anticancer drugs to treat various forms of cancers. Since doxinduced cardiotoxicity is a major limiting factor in the use of dox, new strategies to prevent or reverse the cardiotoxic sideeffects of dox have been explored 1214. Currently, assessing the cardiotoxicity potential is a crucial parameter in drug. Dose reduction protocols have been proposed to avoid the risk of delayed cardiotoxicity, but this might be at the expense of the anticancer effect. In support of this model, an inhibition of mrp2 expression by a bacterial toxin decreased biliary clearance of doxorubicin and increased its plasma concentration. No studies have investigated the effects of cr alone or the combined effects of cr and exercise on dox cardiotoxicity. Pdf mitochondrial catastrophe during doxorubicininduced. Inhibition of the cardiac myocyte mineralocorticoid.
Doxorubicin is a commonly used chemotherapeutic agent for the treatment of a range of cancers, but despite its success in improving cancer survival rates, doxorubicin is cardiotoxic and can lead to congestive heart failure. Beyond its anticoagulant action, enoxaparin enx, a low molecular weight heparin, has been shown to exert multiple pharmacological actions including antioxidant, antiinflammatory and antiapoptotic effects. It is becoming increasingly clear that apoptosis of myocardial cells plays a critical role in the onset of cardiomyopathy. Michaela fojtu, jaromir gumulec, tibor stracina, martina raudenska, anna skotakova, marketa vaculovicova, vojtech adam, petr babula, marie novakova and michal masarik affiliation. In the acute model of doxorubicininduced cardiotoxicity, 6 to 8wkold male c57bl6j mice are injected intraperitoneally with 15 mgkg body wt of. A higher risk for developing doxorubicininduced cardiac injury was observed in postmenopausal women than that in premenopausal women 42. Pdf on jun 1, 1995, l samuel and others published doxorubicininduced cardiotoxicity find, read and cite all the research you need on researchgate. Understanding molecular mechanisms of chemotherapy induced cardiotoxicity is a key to effective preventive strategies and improved chemotherapy regimen. Doxorubicin is a widely used chemotherapy drug, but its application is associated with cardiotoxicity. Department of physiology, faculty of medicine, masaryk university, kamenice 5, cz625 00 brno. The incidence of acute cardiotoxicity is approximately 11% 3,4. The anthracyclines and related compounds doxorubicin, daunorubicin, idarubicin, epirubicin, and the anthraquinone mitoxantrone are among the chemotherapeutic agents implicated in cardiotoxicity. In the acute model of doxorubicin induced cardiotoxicity, 6 to 8wkold male c57bl6j mice are injected intraperitoneally with 15 mgkg body wt of.
Modulation of doxorubicininduced cardiotoxicity by. Animal studies have shown activity in a spectrum of experimental tumors, immunosuppression, carcinogenic properties in rodents. The actual incidence of late cardiotoxicity is dif. Anthracycline cardiotoxicity is known as type 1 cardiotoxicity, characterized by cardiomyocyte death and irreversible cardiac injury. The aim of the present study was to determine whether spirulina, a bluegreen algae, could serve as a. Heparin attenuates doxorubicininduced cardiotoxicity in. Druginduced cardiotoxicity is a major adverse effect that has been encountered for some clinically important drugs especially antineoplastic agents. Anthracyclineinduced cardiomyopathy has been classi. Fndc5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicininduced cardiotoxicity via activating akt. The mechanisms of doxorubicin induced cardiotoxicity remain incompletely understood. Effects of calorie restriction and voluntary exercise on.
Dox exposure to endothelial cells and cardiomyocytes caused apoptotic cell death at submicromolar. This study aimed to investigate whether piperine inhibited doxrelated. 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. Therefore, cardiac mast cells could be important in doxorubicininduced cardiotoxicity. It is widely utilized in the therapy of variety of haematological and solid tumours, although its. The role of autophagy rita zilinyi 1, attila czompa 1, andras czegledi 1, andrea gajtko 2, dora pituk 1, istvan lekli 1 and arpad tosaki 1, 1 department of pharmacology, faculty of pharmacy, university of debrecen, nagyerdei krt 98, 4032 debrecen, hungary. Fndc5 alleviates oxidative stress and cardiomyocyte apoptosis.
Voluntary exercise on doxorubicin induced cardiotoxicity stephanie e. Trpc3nox2 complex mediates doxorubicininduced myocardial atrophy tsukasa shimauchi, 1,2,3 takuro numagatomita, 1,4 tomoya ito, 1 akiyuki nishimura, 1,4 ryosuke matsukane, 1,2 sayaka oda, 1,4 sumio hoka, 3 tomomi ide, 5 norimichi koitabashi, 6 koji uchida, 7 hideki sumimoto, 8 yasuo mori, 9 and motohiro nishida 1,2,4,10. Doxorubicin induced cardiotoxicity is emerging as a critical. Severe cardiotoxicity limits the use of doxorubicin in cancer treatment. Cumulative incidences of cardiac events peaked at 1 year after anthracycline treatment11,12. Receipt of other cardiotoxic chemotherapeutic drugs, such as trastuzumab or cyclophosphamide, significantly increases the chance of cardiotoxicity. Some cancers such as breast cancer even show survival rates of 80%. Teaching the basics of the mechanism of doxorubicininduced.
The metformintreated group received 250 mgkgday metformin via gavage. It is usually evident within 30 days of administration of its last dose, but it may occur even after 610 years after its administration. Druginduced mitochondrial dysfunction and cardiotoxicity. Heparin attenuates doxorubicininduced cardiotoxicity in the. Piperine alleviates doxorubicininduced cardiotoxicity via. The role of ampk activation for cardioprotection in. Several hypotheses have been advanced to explain dox cardiac side effects, which culminate in. The anthracycline antibiotic doxorubicin dox is one of the most effective chemotherapeutic agents in the treatment of numerous solid tumors and hematological malignancies 1,2. Oxidative stress, inflammation and cardiac apoptosis were closely involved in doxorubicin doxinduced cardiac injury.
Lipid emulsion inhibits the late apoptosiscardiotoxicity induced by doxorubicin in rat cardiomyoblasts raghavendra baregundi subbarao 1,2,, seongho ok 2,3, soo hee lee 1, dawon kang 4, eunjin kim 4, jiyoon kim 5 and jutae sohn 1,2, 1 department of anesthesiology and pain medicine, gyeongsang national university school of. Therapeutic options for this patient group are limited to standard heart failure medications with the only drug specific for doxorubicin cardiotoxicity to reach fda. Trpc3nox2 complex mediates doxorubicininduced myocardial. Transcriptional analysis of doxorubicininduced cardiotoxicity. Here, we demonstrate that inhibiting transient receptor potential canonical 3 trpc3 channels abolishes doxorubicin induced myocardial atrophy in mice. Doxorubicin cardiotoxicity can be acute, occurring during and within 23 days of its administration. Prevention and management of anthracycline cardiotoxicity and cardiovascular complications of other classes of chemotherapy agents are discussed separately. However, whether piperine could protect the mice against doxrelated cardiac injury remain unclear. Doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients.
Pdf on nov 14, 2018, danubia silva dos santos and others published doxorubicininduced cardiotoxicity. Based on evidence from both animal models and patient. Teaching the basics of the mechanism of doxorubicin. Enoxaparin attenuates doxorubicin induced cardiotoxicity. The clinical use of doxorubicin, an effective chemotherapeutic is hampered by the development of irreversible cardiotoxicity. Doxorubicin, nanoparticles, liposomal, polymeric, protein, gold, cardiotoxicity, nanocarriers. Doxorubicin, sold under the brand name adriamycin among others, is a chemotherapy medication used to treat cancer. Understanding molecular mechanisms of chemotherapyinduced cardiotoxicity is a key to effective preventive strategies and improved chemotherapy regimen. Doxorubicin dox is a widely used chemotherapeutic agent with known cardiotoxic properties, while calorie restriction cr and exercise have welldocumented cardioprotective effects. Doxorubicin induces cardiotoxicity through upregulation of. Mab 5 mgkg was injected in vivo into c57bl6j mice prior to doxorubicin three doses of 7 mgkg. The incidence of doxorubicin cardiomyopathy is primarily related to its dose. Recently, global longitudinal peak systolic strain gls measures with speckle tracking echocardiography ste and highsensitivity troponin t hstnt have been utilized to evaluate the development of cardiotoxicity. The generation of reactive oxygen species and mitochondrial dysfunction has been implicated in doxorubicin doxinduced cardiotoxicity.
Reduction of doxorubicininduced cardiotoxicity using nanocarriers. In this study we investigated whether the activation of the hgf receptor. Therefore, cardiac mast cells could be important in doxorubicin induced cardiotoxicity. Lombardi cancer research center, georgetown university, washington, o. Nebivolol effect on doxorubicininduced cardiotoxicity in. This toxicity has previously led to the postmarketing withdrawal of numerous pharmacologically active drugs and limits the efficacy of other clinically useful ones. The doxorubicintreated group received doxorubicin 3 mgkg every second day intraperitoneally. Comparison of exercise training and estrogen supplementation. Two mouse models of doxorubicininduced cardiomypathy. Since the first heart failure was reported in children.
Doxorubicin induced apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic effects, toxicities, or both. Acute doxorubicin cardiotoxicity is associated with p53induced inhibition of the mammalian target of rapamycin pathway. The generation of reactive oxygen species and mitochondrial dysfunction has been implicated in doxorubicin dox induced cardiotoxicity. However, its clinical use has been compromised due to its dosedependent cardiotoxicity, which appears to be progressive and permanent 1,3,4. It is often used together with other chemotherapy agents. This includes breast cancer, bladder cancer, kaposis sarcoma, lymphoma, and acute lymphocytic leukemia. These improvements can, in part, be attributed to the impact of chemotherapeutics such as doxorubicin dox, which is an anthracycline antibiotic first. Uk cancer survival rates across all cancer types have doubled in adults and children over the last 40 years and now stand at 50%. From mechanisms to development of efficient therapy find, read and. Protective effects of deep sea water against doxorubicin.
Anthracycline antibiotic doxorubicin dox is a very potent and extensively prescribed chemotherapeutic drug. 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. Anthracycline therapy is associated with an increase in the risk for developing heart failure with significant associated morbidity and mortality 1. Several hypotheses have been advanced to explain dox cardiac side effects, which culminate in the development of life. Animal studies were approved by the institutional animal care and use committee of the university of texas southwestern medical center. Doxorubicin toxicity involves the generation of reactive oxygen species ros and hence several antioxidants and plant products have been tried to minimise the cardiotoxicity. Nov 22, 2012 definition of chemoterapy induced cardiotoxicity. Mar 16, 2017 doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients.
In up to 10% of patients acute doxorubicininduced cardiotoxicity occurs within days after doxorubicin administration. Doxorubicininduced cardiotoxicity is emerging as a critical. Mar 11, 20 doxorubicin dox is an anticancer anthracycline that presents a dose. A higher risk for developing doxorubicin induced cardiac injury was observed in postmenopausal women than that in premenopausal women 42. Dec 11, 2009 the incidence of chronic doxorubicin cardiotoxicity is much lower, with an estimated incidence of about 1. In animal studies, lovastatin attenuated troponin i elevation and cardiac. Free radical generation and mitochondrial dysfunction are thought to contribute to doxorubicininduced cardiac failure 1, 2.
Doxorubicin dox is an anticancer anthracycline that presents a dose. As a representative drug of anthracycline, doxorubicin dox is one of the major culprits in chemotherapy induced cardiotoxicity, which could lead to irreversible degenerative cardiomyopathy and heart failure. A growing body of researches is now studying cardiovascular events associated with chemotherapy, however a clear definition of cardiotoxicity and the certain mechanisms involved are lacking. Piperine has been reported to suppress inflammatory response and pyroptosis in macrophages. Initially, it was widely accepted that doxorubicinin duced cardiotoxicity is completely independent from its anticancer activity. Fndc5 alleviates oxidative stress and cardiomyocyte. Reduction of doxorubicininduced cardiotoxicity using. A prime limitingfactor to the administration of this drugis cardiotoxicity, which frequently develops when the cumulative dose exceeds 500 mgsq m. Reversible doxorubicininduced congestiveheart failure murraycohen,md. Several antioxidants or iron chelators including nacetylcysteine, ascorbic acid, and dexrazoxane have been shown to alleviate anthracyclineinduced cardiotoxicity. Doxorubicininduced apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic effects, toxicities, or both.
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