Molecular Mechanisms of Cardiotoxicity: A Review on Major Side-effect of Doxorubicin (original) (raw)
Related papers
Archives of Toxicology, 2022
A breakthrough in oncology research was the discovery of doxorubicin (Dox) in the 1960’s. Unlike other chemotherapy drugs, Dox was determined to have a greater therapeutic index. Since its discovery, Dox has, in part, contributed to the 5–10-year survival increase in cancer patient outcomes. Unfortunately, despite its efficacy, both in adult and pediatric cancers, the clinical significance of Dox is tainted by its adverse side effects, which usually manifest as cardiotoxicity. The issue stems from Dox’s lack of specificity which prevents it from accurately distinguishing between cancer cells and healthy cell lines, like cardiomyocytes. In addition, the high binding affinity of Dox to topoisomerases, which are abundantly found in cancer and cardiac cells in different isoforms, potentiates DNA damage. In both cell lines, Dox induces cytotoxicity by stimulating the production of pro-oxidants whilst inhibiting antioxidant enzymatic activity. Given that the cardiac muscle has an inherent...
2017
Doxorubicin is useful anticancer drug because it's used in treatment of acute leukemia, Hodgkin's and non-Hodgkin's lymphomas, and many other malignant neoplasm. The mechanism of doxorubicin induce cardiotoxicity is multifactorial includes free radical stress, mitochondrial dysfunction and calcium overload these are the main causes of doxorubicin-induced cardiotoxicity. Doxorubicin therapy augments oxidative stress and disturbs cytosolic calcium homeostasis, increases intracellular calcium levels from the sarcoplasmic reticulum through activation of the ryanodine receptor and by blighting calcium clearance systems in cardiomyocytes. In this condition the researchers trying to develop cardio-protective strategy to decrease this cardio-toxic effect without decreasing its anticancer effect. Now day's oncologists and pharmacologist work to find out how to decrease the cardiovascular risk and prevent doxorubicin adverse cardiovascular effect. Therefore, the aim of this st...
Molecular Pharmacology, 2019
Doxorubicin (DOX) is one of the most effective anticancer drugs to treat various forms of cancers; however, its therapeutic utility is severely limited by its associated cardiotoxicity. 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. In this study, we reviewed literature to gather the best-known molecular pathways related to DOX-induced cardiotoxicity (DIC). They include mechanisms dependent on mitochondrial dysfunction such as DOX influence on the mitochondrial electron transport chain, redox cycling, oxidative stress, calcium dysregulation, and apoptosis pathways. Furthermore, we discuss the existing strategies to prevent and/or alleviate DIC along with various techniques available for therapeutic drug monitoring (TDM) in cancer patients treated with DOX. Finally, we propose a stepwise flowchart for TDM of DOX and present our perspective at curtailing this deleterious side effect of DOX.
Doxorubicin-Induced Cardiotoxicity: From Mechanisms to Development of Efficient Therapy
Cardiotoxicity
First isolated in the early 1960s, doxorubicin (DOX) is among the most effective anticancer agents ever developed. DOX has been used mainly for the treatment of breast cancer, solid tumors in children, soft tissue sarcomas, and aggressive lymphomas. However, the use of DOX may have dose-dependent cardiotoxic effects that generate changes in myocardial structure, which can develop into severe and irreversible cardiomyopathy. Here, we describe the incidence of DOX-induced cardiotoxicity (DIC); the progress made over the past four decades in understanding the molecular mechanisms of the pathogenesis of acute and chronic DIC; the current strategies for heart protection; and the major breakthroughs and challenges in basic and clinical research to the development of efficient targeted therapy for DIC.
Doxorubicin-induced cardiomyopathy: From molecular mechanisms to therapeutic strategies
Journal of Molecular and Cellular Cardiology, 2012
The utility of anthracycline antineoplastic agents in the clinic is compromised by the risk of cardiotoxicity. It has been calculated that approximately 10% of patients treated with doxorubicin or its derivatives will develop cardiac complications up to 10 years after the cessation of chemotherapy. Oxidative stress has been established as the primary cause of cardiotoxicity. However, interventions reducing oxidative stress have not been successful at reducing the incidence of cardiotoxicity in patients treated with doxorubicin. New insights into the cardiomyocyte response to oxidative stress demonstrate that underlying differences between in vitro and in vivo toxicities may modulate the response to superoxide radicals and related compounds. This has led to potentially new uses for pre-existing drugs and new avenues of exploration to find better pharmacotherapies and interventions for the prevention of cardiotoxicity. However, much work still must be done to validate the clinical utility of these new approaches and proposed mechanisms. In this review, the authors have reviewed the molecular mechanisms of the pathogenesis of acute and chronic doxorubicin-induced cardiotoxicity and propose potential pharmacological interventions and treatment options to prevent or reverse this specific type of heart failure.
Life
Doxorubicin (DOX; Adricin) is an anthracycline antibiotic, which is an efficient anticancer chemotherapeutic agent that targets many types of adult and pediatric tumors, such as breast cancer, leukemia, and lymphomas. However, use of DOX is limited due to its cardiotoxic effects. This study sequentially investigated the mechanistic pathways of the cardiotoxic process of DOX in rats at different post-treatment periods using cumulative dose, which is used in therapeutic regimes. In this regard, 56 male albino rats were used for the experiment. The experimental animals were divided into seven groups (n = 8/group) based on dose and sacrifice schedule as follows: G1 (2 mg/kg body weight [BW] and sacrificed at day 4), G2 (4 mg/kg BW and sacrificed at day 8), G3 (6 mg/kg BW and sacrificed at day 15), G4 (8 mg/kg BW and sacrificed at day 30), G5 (10 mg/kg BW and sacrificed at day 60), G6 (10 mg/kg BW and sacrificed at day 90), and G7 (10 mg/kg BW and sacrificed at day 120). As expected, G1,...
A novel insight into the cardiotoxicity of antineoplastic drug doxorubicin
International journal of molecular sciences, 2013
Doxorubicin is a commonly used antineoplastic agent in the treatment of many types of cancer. Little is known about the interactions of doxorubicin with cardiac biomolecules. Serious cardiotoxicity including dilated cardiomyopathy often resulting in a fatal congestive heart failure may occur as a consequence of chemotherapy with doxorubicin. The purpose of this study was to determine the effect of exposure to doxorubicin on the changes in major amino acids in tissue of cardiac muscle (proline, taurine, glutamic acid, arginine, aspartic acid, leucine, glycine, valine, alanine, isoleucine, threonine, lysine and serine). An in vitro interaction study was performed as a comparison of amino acid profiles in heart tissue before and after application of doxorubicin. We found that doxorubicin directly influences myocardial amino acid representation even at low concentrations. In addition, we performed an interaction study that resulted in the determination of breaking points for each of ana...
Doxorubicin-Induced Cardiotoxicity: From Bioenergetic Failure and Cell Death to Cardiomyopathy
Medicinal Research Reviews, 2014
Doxorubicin (DOX) is an anticancer anthracycline that presents a dose-dependent and cumulative cardiotoxicity as one of the most serious side effects. Several hypotheses have been advanced to explain DOX cardiac side effects, which culminate in the development of life-threatening cardiomyopathy. One of the most studied mechanisms involves the activation of DOX molecule into a more reactive semiquinone by mitochondrial Complex I, resulting in increased oxidative stress. The present review describes and critically discusses what is known about some of the potential mechanisms of DOX-induced cardiotoxicity including mitochondrial oxidative damage and loss of cardiomyocytes. We also discuss alterations of mitochondrial metabolism and the unique characteristics of DOX delayed toxicity, which can also interfere on how the cardiac muscle handles a "second-hit stress." We also present pharmaceutical and nonpharmaceutical approaches that may decrease DOX cardiac alterations in animal models and humans and discuss the limitations of each strategy. C 2013 Wiley Periodicals, Inc. Med. Res. Rev., 00, No. 0, 1-30, 2013 2 r CARVALHO ET AL.
Toxicological Sciences, 2014
Many efficacious cancer treatments cause significant cardiac morbidity, yet biomarkers or functional indices of early damage, which would allow monitoring and intervention, are lacking. In this study, we have utilized a rat model of progressive doxorubicin (DOX)-induced cardiomyopathy, applying multiple approaches, including cardiac magnetic resonance imaging (MRI), to provide the most comprehensive characterization to date of the timecourse of serological, pathological, and functional events underlying this toxicity. Hannover Wistar rats were dosed with 1.25 mg/kg DOX weekly for 8 weeks followed by a 4 week off-dosing "recovery" period. Electron microscopy of the myocardium revealed subcellular degeneration and marked mitochondrial changes after a single dose. Histopathological analysis revealed progressive cardiomyocyte degeneration, hypertrophy/cytomegaly, and extensive vacuolation after two doses. Extensive replacement fibrosis (quantified by Sirius red staining) developed during the off-dosing period. Functional indices assessed by cardiac MRI (including left ventricular ejection fraction (LVEF), cardiac output, and E/A ratio) declined progressively, reaching statistical significance after two doses and culminating in "clinical" LV dysfunction by 12 weeks. Significant increases in peak myocardial contrast enhancement and serological cardiac troponin I (cTnI) emerged after eight doses, importantly preceding the LVEF decline to <50%. Troponin I levels positively correlated with delayed and peak gadolinium contrast enhancement, histopathological grading, and diastolic dysfunction. In summary, subcellular cardiomyocyte degeneration was the earliest marker, followed by progressive functional decline and histopathological manifestations. Myocardial contrast enhancement and elevations in cTnI occurred later. However, all indices predated "clinical" LV dysfunction and thus warrant further evaluation as predictive biomarkers.