Modeling doxorubicininduced cardiotoxicity in human. Despite being one of the most potent chemotherapeutics, doxorubicin dox facilitates cardiac toxicity by irreversibly damaging the cardiac muscle as well as severely dysregulating the immune system and impairing the resolution of cardiac inflammation. Nadph oxidase and multidrug resistance protein genetic. Anthracycline therapy is associated with an increase in the risk for developing heart failure with significant associated morbidity and mortality 1. R01 doxorubicininduced respiratory dysfunction and the protective effects of exercise total direct. Anthracycline antibiotic doxorubicin dox is a very potent and extensively prescribed chemotherapeutic drug. A pairwise comparative metabolomics approach was used to delineate the potential metabolic processes in the present study. Herein, we report synthesis and aqueous selfassembly of nanosized polymersomes from temperatureresponsive poly3methylnvinylcaprolactam. Identification of the molecular basis of doxorubicin induced cardiotoxicity. In humans, dox cardiotoxicity manifests over two time scales. However, cumulative dose dependent cardiotoxicity has been a major hurdle where doxorubicin is the primary choice as an antitumor drug. Doxorubicin, sold under the brand name adriamycin among others, is a chemotherapy medication used to treat cancer.
A largescale study that retrospectively evaluated the cardiotoxicity of doxorubicin reported that an. Doxorubicin induced cardiomyopathy typically results in dilated cardiomyopathy, with all four cardiac chambers being enlarged. Principal investigator r01hl146443 512019 4302024 nih. The complex and not completely understood pathogenesis of this complication makes difficult to design successful preventive or curative measures. Department of physiology, faculty of medicine, masaryk university, kamenice 5, cz625 00 brno. Quaking inhibits doxorubicinmediated cardiotoxicity. It has also become apparent that doxorubicin can induce apoptosis via. This results in both systolic and diastolic dysfunction. Cardiotoxicity of doxorubicin treatment and physical activity.
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. Protection from doxorubicininduced cardiac toxicity in. The iron chelator icrf187 has been shown to protect against dox induced cardiotoxicity. Yeh, mdy abstract anthracycline compounds are major culprits in chemotherapyinduced cardiotoxicity, which is the chief limiting factor in. Simvastatin was administrated daily one week before doxorubicin treatment. The incidence of acute cardiotoxicity is approximately 11% 3,4. Reduction of doxorubicininduced cardiotoxicity using nanocarriers.
Development of an effective drug to prevent and treat cardiac toxicity induced by dox. Several recent studies have leveraged hpsccms to develop a mechanistic understanding of doxorubicininduced cardiotoxicity burridge et al. We observed that cardiac enzymes such as ldh and ck were signifi. Genomic prediction of chemotherapyinduced cardiotoxicity. Doxorubicin, nanoparticles, liposomal, polymeric, protein, gold, cardiotoxicity, nanocarriers. There is no specific curative or preventive treatment available.
Oxidative stress is a major cause of doxorubicin induced cardiotoxicity. The anthracyclines and related compounds doxorubicin, daunorubicin, idarubicin, epirubicin, and the anthraquinone mitoxantrone are among the chemotherapeutic agents implicated in cardiotoxicity. Carbonyl reductase cbr has been implicated in the development of doxorubicininduced cardiotoxicity. Mechanism of doxorubicin cardiotoxicity evaluated by. This study investigat ed whether hong huang decoction hhd inhibits doxinduced cardiotoxicity. By danubia silva dos santos and regina coeli dos santos. Doxorubicin is given by injection into a vein common side effects include hair loss, bone marrow suppression. Acute effects occur within 48 h of infusion and are generally reversible and clinically manageable takemura and fujiwara, 2007. Mar 16, 2017 doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients. A largescale study that retrospectively evaluated the cardiotoxicity of doxorubicin reported that an estimated 7% of patients developed doxorubicin. Doxorubicin is a highly effective antineoplastic agent, but it can produce the serious side effects of acute cardiac injury and chronic congestive heart failure.
Propolis doxorubicin cardiotoxicity antioxidant pdf keywords. Doxorubicin cardiotoxicity and the protective effects of exercise total direct costs. At present, adriamycininduced chf can best be prevented by limiting the total dose. Jci cardiotoxicity of doxorubicin is mediated through. Diohf protects against doxorubicininduced cardiotoxicity through. Protective effects of dexrazoxane against doxorubicin.
It is generally accepted that the oxidative stress evoked by doxorubicin activates apoptotic signaling leading to cardiomyocyte apoptosis, and that both the extrinsic and intrinsic apoptoticpathways are involved. Although cardiomyocyte has been considered a classical cellular target, other cells including various types of. Dec 11, 2009 the incidence of chronic doxorubicin cardiotoxicity is much lower, with an estimated incidence of about 1. Mechanistically, qki inhibits doxorubicinmediated cardiotoxicity via regulating cardiac circular rnas. Doxorubicin is a cytotoxic anthracycline antibiotic isolated from cultures of streptomyces peucetius var. 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. Finally, hearts from patients with doxorubicin induced.
Cardiotoxicity is a limiting factor in the treatment of cancer with adriamycin. For language access assistance, contact the ncats public information officer. Modeling trastuzumabrelated cardiotoxicity in vitro using. The lifethreatening toxic side effects are related to cardiotoxicity heart failure, cardiomyopathy that occurs many years after the cessation of. Dox exposure to endothelial cells and cardiomyocytes caused apoptotic cell death at submicromolar. Free radical generation and mitochondrial dysfunction are thought to contribute to doxorubicininduced cardiac failure 1, 2.
Related cardiomyopathy perhaps the most predictive measure of the development of anthracyclinerelated cardiotoxicity is the total cumulative dose. Postmenopausal and hypertensive females are two highrisk groups for developing adverse effects following dox treatment. Animal studies have shown activity in a spectrum of experimental tumors, immunosuppression, carcinogenic properties in rodents. Get a printable copy pdf file of the complete article 883k, or click on a. Finally, hearts from patients with doxorubicininduced cardiomyopathy had markedly higher mitochondrial iron levels than hearts from patients with other types of cardiomyopathies or normal. Doxorubicin cardiotoxicity can be acute, occurring during and within 23 days of its administration. New signal transduction paradigms in anthracyclineinduced. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. Cardioprotective effects of carvedilol in inhibiting doxorubicin induced cardiotoxicity. Doxorubicin dox induced cardiotoxicity limits the use of dox as an antitumor 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.
Doxorubicin, also known as adriamycin or rubex, is an anthracycline antibiotic that was discovered from a mutated strain of streptomyces peucetius. Doxorubicininduced apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic effects, toxicities, or both. The present study investigated whether the practice of exercise has a protective effect against cardiac toxicity induced by doxorubicin dox. Doxorubicin enhances oxysterol levels resulting in a lxr. Propolis doxorubicin cardiotoxicity antioxidant pdf. Ninetysix balbc mice were randomly divided into two supergroups. Aug 01, 2019 anthracyclines cause progressive cardiotoxicity whose ultimate severity is individual to the patient. Genetic and rare diseases information center gard po box 8126, gaithersburg, md 208988126 tollfree. Background anthracycline induced cardiotoxicity is a major clinical problem, and early cardiotoxicity markers are needed. Congestive heart failure in patients treated with doxorubicin.
Uses are limited by dosedependent cardiotoxicity and hepatotoxicity. The mechanisms of doxorubicin induced cardiotoxicity dic remain incompletely understood. Dexrazoxane, a drug that attenuates doxorubicininduced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicininduced cardiac damage. Topoisomerase iibeta mediated dna doublestrand breaks. Early evidence of cardiotoxicity and tumor response in. Data was collected on patients who received 90 mgm 2 doxorubicin as a continuous infusion and 10 gm. The mechanisms of doxorubicininduced cardiotoxicity. This may suggest that endogenous reproductive hormones can in part suppress doxinduced. The incidence of doxorubicin cardiomyopathy is primarily related to its dose. Together, these results provide strong evidence that cyp1 is an important contributor to doxorubicin. Prevention of anthracyclineinduced cardiotoxicity challenges and opportunities pimprapa vejpongsa, md, edward t. The pathogenesis of doxorubicin induced cardiotoxicity is complex and multifactorial.
Doxorubicin hydrochloride for injection, usp patient. This study investigated the potential cardioprotective effects of rsvl against dox induced cardiotoxicity. Michaela fojtu, jaromir gumulec, tibor stracina, martina raudenska, anna skotakova, marketa vaculovicova, vojtech adam, petr babula, marie novakova and michal masarik affiliation. Nabati m, janbabai g, baghyari s, esmaili m, yazdani j. Doxorubicin induced heart failure can appear very late after the last administration. Cardioprotection of dexrazoxane dzr against doxorubicin doxinduced cardiotoxicity is contentious and the indicator is controversial. Importantly, genetic mutation of cyp1a protected zebrafish against doxorubicin.
Doxorubicin is a highly efficacious anticancer drug but causes cardiotoxicity in many patients. The cardiotoxicity of doxorubicin is becoming an interdisciplinary point of interest given a growing population of cancer survivors. Carbonyl reductase cbr has been implicated in the development of doxorubicin induced cardiotoxicity. Role of micrornas in doxorubicininduced cardiotoxicity. Doxorubicininduced cardiotoxicity is suppressed by. The mechanisms of doxorubicin induced cardiotoxicity remain incompletely understood. Pdf on nov 14, 2018, danubia silva dos santos and others published doxorubicininduced cardiotoxicity. Objectives the purpose of this study was to identify early doxorubicininduced cardiotoxicity by serial multiparametric cardiac magnetic resonance cmr and its pathological correlates in a large animal model. Methods the authors declare that all supporting data are availa ble within the article and its online supplementary files. 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.
Doxorubicininduced cardiotoxicity in collaborative cross cc. However, its clinical success is limited because it increases hematotoxicity in cancer patients 14,15. Doxorubicin, heart, liver, lipid peroxidation, propolis extract, vinblastin. Doxorubicin has been used extensively for the treatment of hematological cancers, cancers of breast, lung and bone, and soft tissue sarcomas. Despite the dosedependent response rate of sarcomas to doxorubicin, clinicians limit its cumulative dose due to cardiotoxicity. Diohf suppresses and reverses the doxinduced cardiotoxicity by inhibiting ros release, stabilizing mitochondrial function and. Serial magnetic resonance imaging to identify early stages of. Background anthracyclineinduced cardiotoxicity is a major clinical problem, and early cardiotoxicity markers are needed. Doxorubicin induced apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic effects, toxicities, or both.
This study evaluates early evidence of cardiotoxicity in patients treated with highdose doxorubicin given as a continuous infusion. Temperatureresponsive polymersomes of poly3methyln. An overview of all apoptotic pathways involved in doxorubicininduced cardiotoxicity is given in fig. Reduction of doxorubicininduced cardiotoxicity using. Among the most cardiotoxic agents are anthracyclines, such as doxorubicin, epirubicin and daunorubicin, that. Doxorubicin doxinduced cardiotoxicity limits the use of dox as an antitumor drug. Teaching the basics of the mechanism of doxorubicininduced. Although multiple mechanisms are involved in doxorubicininduced cardiotoxicity, generation of ros which causes lipid peroxidation and depletion of antioxidant enzymes is considered as the major. Quaking inhibits doxorubicinmediated cardiotoxicity through. Doxorubicininduced cardiotoxicity in collaborative cross. Anthracyclines cause progressive cardiotoxicity whose ultimate severity is individual to the patient. From mechanisms to development of efficient therapy. Doxorubicin consists of a naphthacenequinone nucleus linked through a glycosidic bond at ring atom 7 to an amino sugar, daunosamine. 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.
This study investigat ed whether hong huang decoction hhd inhibits dox induced cardiotoxicity. Molecular mechanism and protection by conventional drugs and natural products. Finally, hearts from patients with doxorubicininduced. If you have problems viewing pdf files, download the latest version of adobe reader. Original article simvastatin protects cardiomyocytes from. It is becoming increasingly clear that apoptosis of myocardial cells plays a critical role in the onset of cardiomyopathy.
Objectives the purpose of this study was to identify early doxorubicin induced cardiotoxicity by serial multiparametric cardiac magnetic resonance cmr and its pathological correlates in a large animal model. We then update the findings of molecular biology of doxinduced cardiomyopathy including molecular mechanisms, established and putative. Doxorubicin dox, an anthracycline therapeutic, is widely used to treat a variety of cancer types and known to induce cardiomyopathy in a time and dosedependent manner. Attenuation of doxorubicininduced cardiotoxicity in a human in vitro cardiac model. Genetic determinants contributing to this variation are difficult to study using current mouse models. 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. Doxorubicininduced cardiotoxicity in adult indian patients on chemotherapy article pdf available in indian journal of medical and paediatric oncology 301. Dexrazoxane, a drug that attenuates doxorubicin induced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicin induced cardiac damage. Review of trastuzumabinduced cardiotoxicity in elderly treatment of chemotherapyinduced cardiotoxicity 3. In support of this model, an inhibition of mrp2 expression by a bacterial toxin decreased biliary clearance of doxorubicin and increased its plasma concentration. It is usually evident within 30 days of administration of its last dose, but it may occur even after 610 years after its administration. 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.
This includes breast cancer, bladder cancer, kaposis sarcoma, lymphoma, and acute lymphocytic leukemia. It is widely utilized in the therapy of variety of haematological and solid tumours, although its. Doxorubicininduced cardiotoxicity is mediated by top2. Prevention of anthracycline induced cardiotoxicity challenges and opportunities pimprapa vejpongsa, md, edward t. Siog apac 2014 12 th to th july breast cancer in older adults cardiac toxicity in breast cancer. Attenuation of doxorubicininduced cardiotoxicity in a human in vitro.
Doxorubicin dox is the predominant anthracycline, but its use is limited due to cardiotoxicity octavia et al. Several recent studies have leveraged hpsccms to develop a mechanistic understanding of doxorubicin induced cardiotoxicity burridge et al. It is often used together with other chemotherapy agents. To determine antioxidant activity of biological samples, and the. Cardioprotective effects of carvedilol in inhibiting doxorubicininduced cardiotoxicity. Protection from doxorubicininduced cardiac toxicity in mice. Doxorubicin induced cardiomyopathy genetic and rare. Effect of desferrioxamine on doxorubicininduced cardiotoxicity and haematotoxicity in mice. Original article alleviation of doxorubicininduced. Alleviation of doxorubicininduced cardiotoxicity by hong huang. Doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients. Doxorubicin is a widely used chemotherapy drug, but its application is associated with cardiotoxicity. Doxorubicin induces cardiotoxicity through upregulation of.
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