ABSTRACT Anthracycline-based antineoplastic therapy is the standard of care for various cancers today and represents a breakthrough in this area. The cardiac toxicity of anthracyclines is well established. The acute form is often reversible and has no predictive value for the future. This early form does not prevent continuation of chemotherapy. Late cardiac toxicity due to anthracycline is the leading limiting factor in its use. In adults, this resembles dilated cardiomyopathy, while in children it may be expressed as restrictive cardiomyopathy. The discovery of modifiable risk factors has made it possible to identify patients at high risk of developing late cardiac toxicity and heart failure. Because left ventricular dysfunction and heart failure may develop long after anthracycline treatment ends, prolonged close follow-up is mandatory in asymptomatic subjects. Follow-up of asymptomatic patients requires serial echocardiography (M-mode, 2D echo, Doppler, tissue Doppler, speckle tracking, etc.). Anthracycline-induced cardiomyopathy must be treated according to the standard guidelines for chronic heart failure with left ventricular dysfunction, by angiotensin-converting enzyme (ACE) inhibitors and beta-blockers. Lifestyle changes may reduce the long-term risk. Close collaboration between cardiologists and oncologists is highly desirable for optimizing management of these patients.
- SourceAvailable from: Dongmei Ren
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- "Although doxorubicin is an effective anticancer chemotherapeutic agent, its clinical use is limited by cumulative dose-related cardiotoxicity, which may lead to severe and irreversible cardiomyopathy (Gewirtz, 1999; Kim et al., 2006a) and heart failure (Keefe, 2001). A proposed mechanism of cardiotoxicity of doxorubicin is that it causes cardiomyocyte apoptosis. "
ABSTRACT: Doxorubicin, a widely used chemotherapeutic agent, can give rise to severe cardiotoxicity by inducing cardiomyocyte apoptosis. Dracocephalum rupestre Hance, a Chinese traditional herb, has therapeutic potential for cardiovascular diseases. Naringenin-7-O-glucoside is the main active constituent of D. rupestre and there is increasing interest in its therapeutic applications. The aim of this study was to evaluate the effects of naringenin-7-O-glucoside on cardiomyocyte apoptosis induced by doxorubicin. Cell viability was detected by MTT assay. Naringenin-7-O-glucoside (10, 20, and 40 microM) significantly enhanced cardiomyocyte proliferation relative to that of doxorubicin. Furthermore, naringenin-7-O-glucoside increased the protein levels of heme oxygenase-1 (HO-1) and Bcl-2 in cardiomyocytes (as detected by Western blotting) and suppressed the mRNA expression of caspase-3 and caspase-9 (as detected by RT-PCR). These results suggest that naringenin-7-O-glucoside has protective effects against doxorubicin-induced apoptosis, effects which could underlie the use of naringenin-7-O-glucoside therapeutic agent for treating or preventing cardiomyopathy associated with doxorubicin.European Journal of Pharmacology 03/2008; 581(1-2):47-53. DOI:10.1016/j.ejphar.2007.11.048 · 2.68 Impact Factor
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- "Doxorubicin, a quinone-containing anthracycline, is widely used as a chemotherapeutic agent for the treatment of a large spectrum of human neoplasic diseases but its administration in humans is limited by the risk of severe cardiotoxicity . This results from an impaired contractile function and subsequent development of cardiomyopathies secondary to apoptotic cell death    with ceramide accumulation, mitochondrial dysfunction, cytochrome c release [2,5–7] and generation of reactive oxygen species . Our group has previously demonstrated that doxorubicin activates a current electrophysiologically characterized as a volume-sensitive chloride channel (I Cl,vol ) . "
ABSTRACT: Contractile dysfunction and cardiomyopathies secondary to apoptotic cell death are limiting factors for treating cancer with doxorubicin. Inhibition of volume-sensitive chloride currents (I(Cl,vol)) has been reported to blunt doxorubicin-induced apoptosis in cardiomyocytes. To investigate cellular contractility during acute induction of apoptosis by doxorubicin and to determine whether I(Cl,vol) inhibitors are able to prevent the subsequent contractile dysfunction, electrically paced ventricular myocytes freshly isolated from adult rabbits were acutely exposed to doxorubicin in the presence and absence of I(Cl,vol) inhibitors IAA-94 or DIDS. Doxorubicin induced increases in both annexin V labelling and caspase-3 activity and decreases in cell volume. Alteration in cardiac contractility was observed after doxorubicin exposure. Both IAA-94 and DIDS abolished the doxorubicin-induced decreases in peak shortening and cell volume as well as the increases in caspase-3 activity and annexin V labelling. These protective effects of I(Cl,vol) inhibitors were abolished by previous inhibition of PI(3)kinase, Akt and Erk 1/2. Thus, I(Cl,vol) inhibitors prevent doxorubicin-induced apoptosis and subsequent contractile dysfunction through PI(3)kinase/Akt and Erk 1/2. Inhibition of I(Cl,vol) may represent a new pharmacological strategy for developing cytoprotective drugs against apoptotic cell death and contractile dysfunction.European Journal of Heart Failure 02/2008; 10(1):39-46. DOI:10.1016/j.ejheart.2007.11.002 · 6.58 Impact Factor
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- "Doxorubicin (DOX) and other anthracyclines are potent and effective chemotherapeutic agents, but they are associated with a dose-dependent cardiotoxicity, which is the most important factor limiting their clinical use  . The cardiotoxicity can take two major forms. "
ABSTRACT: The clinical use of doxorubicin (DOX) and other anthracyclines is limited by a dosage-dependent cardiotoxicity, which can lead to cardiomyopathy. The role of the individual genetic makeup in this disorder is poorly understood. Alterations in genes encoding cardiac cytoskeleton or sarcolemma proteins may increase the susceptibility to doxorubicin-related cardiotoxicity. Female dystrophin-deficient mice (MDX) and age-matched wild-type mice underwent chronic treatment with doxorubicin. Cardiac function and tissue damage were assessed by echocardiography and histopathology, respectively. Gene expression changes were investigated using microarrays. DOX treatment resulted in mortality, cardiac insufficiency, and cardiac interstitial fibrosis. These alterations were more pronounced in DOX-treated MDX mice than in DOX-treated wild-type mice. Changes in gene expression were more numerous in MDX mice, including genes involved in cell adhesion, oxidative stress, cytoskeleton organization, inflammatory and immune response and cell death. Dystrophin deficiency facilitates the development and progression of doxorubicin-induced cardiac injury. The underlying mechanisms may involve changes in cell adhesion, in cytoskeleton, as well as in inflammatory and immune responses. Genetic variants of cytoskeletal proteins in humans may affect the individual susceptibility to doxorubicin. Cardiotoxic drugs may accelerate the manifestation of pre-clinical cardiomyopathies caused by deficiencies in cytoskeletal or sarcolemma proteins.European Journal of Heart Failure 11/2007; 9(10):986-94. DOI:10.1016/j.ejheart.2007.07.016 · 6.58 Impact Factor