Severe cardiotoxicity limits the use of doxorubicin in cancer treatment. Pristimerin protects against doxorubicininduced cardiotoxicity and fibrosis through modulation of nrf2 and mapknfkappab signaling pathways dina s elagamy,1,2 khaled m elharbi,3 saad khoshhal,3 nishat ahmed,1 mohamed a elkablawy,4,5 ahmed a shaaban,2,6 hany m abohaded3,7 1department of pharmacology and toxicology, college of pharmacy, taibah university, almadinah almunawwarah. The incidence of clinical heart failure during doxorubicin treatment in three studies comprising 630 patients with breast and lung cancer rose exponentially from 5% with a cumulative dose of 400 mgm 2 to 48% with 700 mgm 2. The mechanisms of doxorubicininduced cardiotoxicity. Risk factors that predispose patients to cardiomyopathy include advanced age, previous radiotherapy to the mediastinum, and concurrent cyclophosphamide therapy 2. Teaching the basics of the mechanism of doxorubicin. Aug 05, 2014 another influential factor in chemotherapyinduced cardiotoxicity is the peak serum concentration reached during administration. Doxorubicin is a dna interchelator that inhibits topoisomerase ii thereby inhibiting cancer cell growth. It is a potent anthracycline antibiotic first discovered from the actinobacteria streptomyces peucetius in the 1960s. Anthracycline therapy is associated with an increase in the risk for developing heart failure with significant associated morbidity and mortality 1. Highly potent visnagin derivatives inhibit cyp1 and. The anthracyclines and related compounds doxorubicin, daunorubicin, idarubicin, epirubicin, and the anthraquinone mitoxantrone are among the chemotherapeutic agents implicated in cardiotoxicity.
Reduction of doxorubicin cardiotoxicity by prolonged. Doxorubicin cardiotoxicity and melphalan annals of internal. In the current study using p53 mouse models, lowdose doxorubicin as administered in the clinics surprisingly revealed that the absence of p53 increases susceptibility to doxorubicin cardiotoxicity while a mutant of. Moreover, these studies support the idea that cyp1 is an important contributor to doxorubicin cardiotoxicity and suggest that modulation of this pathway could be beneficial in the clinical setting. Resveratrol attenuates doxorubicin induced cardiotoxicity in rats by upregulation of vascular endothelial growth factor b. Pdf insights into mechanisms of doxorubicin cardiotoxicity. Adriamycin doxorubicin hydrochloride is an antineoplastic agent effective against a wide range of malignant conditions, although cardiac toxicity, especially dosedependent cardiomyopathy, limits its longterm use. Dec 11, 2009 doxorubicin cardiotoxicity can be acute, occurring during and within 23 days of its administration. The mechanisms of doxorubicin induced cardiotoxicity remain incompletely understood. However, in a large metaanalysis by van dalen et al. Scherrercrosbie, in anticancer treatments and cardiotoxicity, 2017. The median cumulative dose for those receiving continuous infusion was 600 mgm 2 body surface area range, 360 to 1500 mgm 2 compared with 465 mgm 2 range, 290 to 680 mgm 2 in the control group p 0. Jci insight mitochondriadependent ferroptosis plays a.
Oxidative stress is a major cause of doxorubicininduced cardiotoxicity. Doxorubicin is a highly efficacious anticancer drug but causes cardiotoxicity in many patients. Chen, 1,3 anita vohra, 2 an chi, 4 ivan cornellataracido, 4 huijun wang, 4 douglas g. We previously identified visnagin as protecting against doxorubicin toxicity in cardiac but not tumor cells. Doxorubicin is a dnadamaging agent that is highly effective against various types of cancers, but a subset of treated patients develop heart failure for unclear genetic reasons. This includes breast cancer, bladder cancer, kaposis sarcoma, lymphoma, and acute lymphocytic leukemia. Dox is a quinonecontaining anthracycline family of drugs. Pdf doxorubicininduced cardiotoxicity researchgate. Cardiotoxicity of chemotherapeutic agents springerlink. It is routinely used in the clinic as a chemotherapeutic agent for the treatment for various cancers including both solid and hematological malignancies. Mar 16, 2017 doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients. Doxorubicin induces cardiotoxicity through upregulation of.
Pdf repeated remote ischemic conditioning protects against. Another influential factor in chemotherapyinduced cardiotoxicity is the peak serum concentration reached during administration. Age has been proven to have cardioprotective effect against doxinduced cardiotoxicity. Doxorubicin cardiotoxicity is associated with the generation of free radicals, and involves not only lipid. Cardiotoxic side effects limit their dosing and improved cancer outcomes expose the cancer survivor to increased cardiovascular morbidity and mortality. Both groups were studied prospectively and were well matched by risk factors for doxorubicin cardiotoxicity. Jci cardiotoxicity of doxorubicin is mediated through.
In a network metaanalysis, the ranking order of cardiotoxicity was doxorubicin worst, epirubicin, dd, ld, and ed best. Doxorubicin showed better activity than daunorubicin against mouse tumors, and especially solid tumors. Other agents that may induce a cardiac event include paclitaxel, etoposide, teniposide, the vinca. Our objective was to determine whether a spectrum of anthracycline induced cardiac disease can be elicited across 10 collaborative cross mouse strains given the same dose of doxorubicin. As the population of cancer survivors who have been.
Other agents that may induce a cardiac event include paclitaxel, etoposide, teniposide. Mechanisms of cardioprotective effect of aged garlic. Jci insight highly potent visnagin derivatives inhibit cyp1. Highly potent visnagin derivatives inhibit cyp1 and prevent doxorubicin cardiotoxicity aarti asnani, 1,2 baohui zheng, 1 yan liu, 1 you wang, 1 howard h. Doxorubicin toxicity involves the generation of reactive oxygen species ros and hence several antioxidants and plant products have been tried to minimise the cardiotoxicity. Druginduced mitochondrial dysfunction and cardiotoxicity. The anticancer drug doxorubicin dox also referred to as adriamycin is highly effective in the treatment of a broad range of cancers. Doxorubicin is effective in controlling a wide variety of canine and feline tumors table 15. Defining cardiotoxicity of doxorubicin and trastuzumab. Modeling doxorubicininduced cardiotoxicity in human. Doxorubicin can cause fetal harm when administered to a pregnant woman. Lymphoma is especially sensitive to doxorubicin and the prognosis improves if the multiagent protocol includes doxorubicin. Sexual dimorphism of doxorubicinmediated cardiotoxicity. Dox undergoes redox cycling which results in enhanced production of reactive oxygen species ros, mitochondrial depolarization and subsequent apoptosis 2.
Jci insight highly potent visnagin derivatives inhibit. It also showed a higher therapeutic index, yet the cardiotoxicity remained. With doxorubicin, the cardiotoxicity likely is dosedependent 197,204 and can develop within days after exposure to the drug 205,206 or months to years after drug treatment 193,195,207. No studies have investigated the effects of cr alone or the combined effects of cr and exercise on dox cardiotoxicity. Early detection of anthracycline cardiotoxicity and. The mechanisms of doxorubicin induced cardiotoxicity dic remain incompletely understood. Cancer management and research nebivolol effect on doxorubicininduced cardiotoxicity in breast cancer flavia cochera 0 daniel dinca 0 0 cardiology department, victor babes university of medicine and pharmacy, timisoara, romania 8 1 0 2 l u j 7 1 n o 7 0 2. Dec 31, 2019 studies have suggested that concomitant administration of doxorubicin and calcium channel entry blockers or cardiotoxic drugs, especially those with long halflives, e. The manifestations are usually chest pain due to myopericarditis andor palpitations due to sinus tachycardia, paroxysmal nonsustained supraventricular tachycardia and. Previously, anthracyclineinduced cardiotoxicity was primarily attributed to irondependent generation of reactive oxygen species and subsequent oxidative damage. Doxorubicin and daunorubicin can cause dosedependent cardiomyopathy in children and adults 1, 2. Modulation of doxorubicininduced cardiotoxicity by. Doxorubicin is a cytotoxic anthracycline antibiotic isolated from cultures of streptomyces peucetius var. Followup cardiac evaluations are recommended periodically to monitor for this effect.
Anthracycline chemotherapy maintains a prominent role in treating many forms of cancer. Anthracyclines cause progressive cardiotoxicity whose ultimate severity is individual to the patient. Drug schedule relative university of wisconsinmadison. Endomyocardial biopsy specimens and test results of cardiac function were obtained before, during, and after treatment. The manifestations are usually chest pain due to myopericarditis andor palpitations due to sinus tachycardia, paroxysmal nonsustained supraventricular tachycardia and premature atrial and ventricular. The authors declare that they have no conflict of interest. So the present study was designed to investigate how age could. It is often used together with other chemotherapy agents. Anthracyclines are among the most widely used chemotherapeutic agents and have been shown to be effective in a wide range of tumors, in particular, breast cancer and lymphoma. Alkylating agents such as cyclophosphamide, ifosfamide, cisplatin, carmustine, busulfan, chlormethine and mitomycin have also been associated with cardiotoxicity. Oct 19, 2012 cytostatic antibiotics of the anthracycline class are the best known of the chemotherapeutic agents that cause cardiotoxicity. First published january 2, 2014 citation information. Anthracycline chemotherapy and cardiotoxicity springerlink. A largescale study that retrospectively evaluated the cardiotoxicity of doxorubicin reported that an.
Polyphenols, autophagy and doxorubicininduced cardiotoxicity. The biopsy specimens were examined by light and electron microscopy and were graded. Mar 15, 2019 previously, anthracyclineinduced cardiotoxicity was primarily attributed to irondependent generation of reactive oxygen species and subsequent oxidative damage. Deficits of mitochondrial function, biogenesis, and energy metabolism have recently emerged as key contributors to heart failure. May 06, 2014 the anticancer drug doxorubicin dox also referred to as adriamycin is highly effective in the treatment of a broad range of cancers.
Liposomal doxorubicin based chemotherapy was associated with a significant reduction in the risk of cardiotoxicity or 0. The incidence of acute cardiotoxicity is approximately 11% 3,4. Doxorubicin and daunorubicin together can be thought of as prototype compounds for the anthracyclines. Both of these studies emphasize the critical role of iron in the pathogenesis of doxorubicininduced cardiotoxicity. Genetic determinants contributing to this variation are difficult to study using current mouse models. This cardiotoxicity often limits chemotherapy for malignancies and is associated with poor prognosis. Doxorubicin dox, a chemotherapeutic agent, induces a cardiotoxicity referred to as doxorubicin induced cardiomyopathy dic. Doxorubicin is an important anticancer drug in the clinic. Transcriptomic profiling reveals p53 as a key regulator of. Molecular mechanisms of doxorubicininduced cardiotoxicity. Doxorubicin dox is a widely used chemotherapeutic agent with known cardiotoxic properties, while calorie restriction cr and exercise have welldocumented cardioprotective effects.
Doxorubicin can be reduced to a semiquinone not depicted by nadph oxidase or enos. Doxorubicin is a highly effective and widely used cytotoxic agent with application that is limited by cardiotoxicity related to the cumulative dose of the drug. Rats were divided into 4 groups based on their food intake ad libitum. Doxorubicin was excreted in the milk of one lactating patient, with peak milk concentration at 24 hours after treatment being approxi er therapy with 70 mgm. Pdf repeated remote ischemic conditioning protects. In this study, we sought to develop more potent visnagin analogs in order to use these analogs as tools to clarify the mechanisms of visnaginmediated cardioprotection. Nebivolol effect on doxorubicininduced cardiotoxicity in. Find, read and cite all the research you need on researchgate. Cardiotoxicity is defined as toxicity that affects the heart by the us national cancer institute 1. Congestive heart failure in patients treated with doxorubicin. Efficacy and cardiotoxicity of liposomal doxorubicinbased. Doxorubicininduced cardiotoxicity in collaborative cross.
Insights into mechanisms of doxorubicin cardiotoxicity. Anthracyclines such as doxorubicin are highly effective chemotherapy agents used to treat many common malignancies. Doxorubicin, whose doselimiting toxicity is cardiomyopathy, was given to four cancer patients. The cardiotoxicity of doxorubicin is becoming an interdisciplinary point of interest given a growing population of cancer survivors. Doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients. Effects of calorie restriction and voluntary exercise on. Doxorubicin is given by injection into a vein common side effects include hair loss, bone marrow suppression. Cardiotoxicity from drug developmental perspective. Wed like to understand how you use our websites in order to improve them. The cause of doxinduced cardiotoxicity is multifactorial and includes free radicalinduced.
Proposed mechanisms of doxorubicin doxinduced cardiotoxicity. The overall incidence of cardiotoxicity in adults receiving standard doses of doxorubicin is relatively low 199. At multivariable analysis, endchemotherapy lvef hazard ratio, 1. Download fulltext pdf anthracycline chemotherapy and cardiotoxicity article pdf available in cardiovascular drugs and therapy 311 february 2017 with 376 reads. Aug 01, 2019 anthracyclines cause progressive cardiotoxicity whose ultimate severity is individual to the patient. Although simple to understand in theory, this definition is very broad and in the case of cancer treatments, may encompass many effects, such as cardiac dysfunction and heart failure, myocardial ischemia or. Cardiotoxicity is a wellrecognized side effect of anthracycline therapy that limits the total amount of drug administered and can cause heart failure. Unfortunately, it causes cumulative and dosedependent cardiotoxic side effects. Jul 23, 2015 liposomal doxorubicin based chemotherapy was associated with a significant reduction in the risk of cardiotoxicity or 0. Liposomal doxorubicinbased chemotherapy was associated with a significant reduction in the risk of cardiotoxicity or 0.
Subsequent research has led to many other anthracycline. Doxorubicin on a weekly schedule 2 or prolonged infusions 3 allow exceeding these limits to a variable degree. Cardiotoxicity accounted for 45% of all drugs withdrawn between 1994 and 2006, which was due mainly to cardiac ischemiarelated and arrhythmogenic side effects. Cardiac toxicity is a major complication which limits the use of adriamycin as a chemotherapeutic agent cardiomyopathy is frequent when the total dose exceeds 600 mgm2 and occurs within one to six months after cessation of therapy. Cytostatic antibiotics of the anthracycline class are the best known of the chemotherapeutic agents that cause cardiotoxicity. Although cardiomyocyte has been considered a classical cellular target, other cells including various types of.
Doxorubicininduced heart failure can appear very late after the last administration. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation yoshihiko ichikawa, tejaswitha jairaj naik, hossein ardehali published february 3, 2014. Doxorubicin induces cardiotoxicity through upregulation of death. Attenuation of doxorubicininduced cardiotoxicity in a human in vitro. Doxorubicininduced cardiotoxicity in collaborative cross cc. The mechanisms of doxorubicininduced cardiotoxicity remain incompletely understood.
Primarily, cardiotoxic drugs may induce cardiovascular adverse effects in a. Teaching the basics of the mechanism of doxorubicininduced. The basic mechanisms of cardiotoxicity may involve direct pathways for reactive oxygen species generation and topoisomerase 2 as well as other indirect. The exact pathogenesis of doxinduced cardiotoxicity remains to be fully elucidated. The incidence of acute cardiotoxicity is approximately 11% 3, 4. Cardioprotectors 4 and liposomal preparations with the potential for reduced toxicity relative to free doxorubicin 57, represent another potential solution to the problem of cardiotoxicity.
However, the molecular mechanism underlying this cardiotoxicity is yet to be fully elucidated. Doxorubicin was teratogenic and embryotoxic at doses of 0. Doxorubicin, sold under the brand name adriamycin among others, is a chemotherapy medication used to treat cancer. Children and adolescents are at an increased risk for developing delayed cardiotoxicity following doxorubicin administration. However, the dosedependent cardiotoxic effects of doxorubicin can limit patient.
The cause of doxinduced cardiotoxicity is multifactorial and. Doxorubicin is a cell cyclenonspecific drug but is most active in the s phase. 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. Doxorubicin hydrochloride is an orangered, crystalline, hygroscopic powder that is soluble in water and slightly soluble in methanol.
Jun 12, 2019 doxorubicin is an important anticancer drug in the clinic. Resveratrol attenuates doxorubicininduced cardiotoxicity. The complex and not completely understood pathogenesis of this complication makes difficult to design successful preventive or curative measures. Request pdf on may 20, 2019, abir khan and others published defining cardiotoxicity of doxorubicin and trastuzumab. Doxorubicin cardiotoxicity can be acute, occurring during and within 23 days of its administration. 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. A patient is reported who developed progressive cardiomyopathy two and onehalf years after receiving 580 mgm2 which apparently represents late, late cardiotoxicity.
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