Cardiotoxicity of Anthracyclines.
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ABSTRACT:
SUBMITTER: Cardinale D
PROVIDER: S-EPMC7093379 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
Cardiotoxicity of Anthracyclines.
Cardinale Daniela D Iacopo Fabiani F Cipolla Carlo Maria CM
Frontiers in cardiovascular medicine 20200318
Cardiotoxicity is a feared side effect that may limit the clinical use of anthracyclines. It may indeed affect the quality of life and survival of patients with cancer, regardless of oncological prognosis. This paper provides an overview of anthracycline-induced cardiotoxicity in terms of definition, classification, incidence, risk factors, possible mechanisms, diagnosis, and treatment. We also report effective strategies for preventing cardiotoxicity. In addition, we discuss limiting current ap ...[more]
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Project description:Anthracyclines are commonly used anticancer drugs with well?known and extensively studied cardiotoxic effects in humans. In the clinical setting guidelines for assessing cardiotoxicity are well?established with important therapeutic implications. Cardiotoxicity in terms of impairment of cardiac function is largely diagnosed by echocardiography and based on objective metrics of cardiac function. Until this day, cardiotoxicity is not an endpoint in the current general toxicology and safety pharmacology preclinical studies, although other classes of drugs apart from anthracyclines, along with everyday chemicals have been shown to manifest cardiotoxic properties. Also, in the relevant literature there are not well?established objective criteria or reference values in order to uniformly characterize cardiotoxic adverse effects in animal models. This in depth review focuses on the evaluation of two important echocardiographic indices, namely ejection fraction and fractional shortening, in the literature concerning anthracycline administration to rats as the reference laboratory animal model. The analysis of the gathered data gives promising results and solid prospects for both, defining anthracycline cardiotoxicity objective values and delineating the guidelines for assessing cardiotoxicity as a separate hazard class in animal preclinical studies for regulatory purposes.
| S-EPMC7388356 | biostudies-literature
Project description:TOP2 inhibitors (TOP2i) are effective drugs for breast cancer treatment. However, they can cause cardiotoxicity in some women. The most widely used TOP2i include anthracyclines (AC) Doxorubicin (DOX), Daunorubicin (DNR), Epirubicin (EPI), and the anthraquinone Mitoxantrone (MTX). It is unclear whether women would experience the same adverse effects from all drugs in this class, or if specific drugs would be preferable for certain individuals based on their cardiotoxicity risk profile. To investigate this, we studied the effects of treatment of DOX, DNR, EPI, MTX, and an unrelated monoclonal antibody Trastuzumab (TRZ) on iPSC-derived cardiomyocytes (iPSC-CMs) from six healthy females. All TOP2i induce cell death at concentrations observed in cancer patient serum, while TRZ does not. A sub-lethal dose of all TOP2i induces limited cellular stress but affects calcium handling, a function critical for cardiomyocyte contraction. TOP2i induce thousands of gene expression changes over time, giving rise to four distinct gene expression response signatures, denoted as TOP2i early-acute, early-sustained, and late response genes, and non-response genes. There is no drug- or AC-specific signature. TOP2i early response genes are enriched in chromatin regulators, which mediate AC sensitivity across breast cancer patients. However, there is increased transcriptional variability between individuals following AC treatments. To investigate potential genetic effects on response variability, we first identified a reported set of expression quantitative trait loci (eQTLs) uncovered following DOX treatment in iPSC-CMs. Indeed, DOX response eQTLs are enriched in genes that respond to all TOP2i. Next, we identified 38 genes in loci associated with AC toxicity by GWAS or TWAS. Two thirds of the genes that respond to at least one TOP2i, respond to all ACs with the same direction of effect. Our data demonstrate that TOP2i induce thousands of shared gene expression changes in cardiomyocytes, including genes near SNPs associated with inter-individual variation in response to DOX treatment and AC-induced cardiotoxicity.
2024-02-01 | GSE243674 | GEO
Project description:BackgroundIn patients treated with cardiotoxic chemotherapies, the presence of cardiovascular risk factors and previous cardiac disease have been strongly correlated to the onset of cardiotoxicity. The influence of overweight and obesity as risk factors in the development of treatment-related cardiotoxicity in breast cancer (BC) was recently suggested. However, due to meta-analysis design, it was not possible to take into account associated cardiac risk factors or other classic risk factors for anthracycline (antineoplastic antibiotic) and trastuzumab (monoclonal antibody) cardiotoxicity.Methods and findingsUsing prospective data collected from 2012-2014 in the French national multicenter prospective CANTO (CANcer TOxicities) study of 26 French cancer centers, we aimed to examine the association of body mass index (BMI) and cardiotoxicity (defined as a reduction in left ventricular ejection fraction [LVEF] > 10 percentage points from baseline to LVEF < 50%). In total, 929 patients with stage I-III BC (mean age 52 ± 11 years, mean BMI 25.6 ± 5.1 kg/m2, 42% with 1 or more cardiovascular risk factors) treated with anthracycline (86% epirubicin, 7% doxorubicin) and/or trastuzumab (36%), with LVEF measurement at baseline and at least 1 assessment post-chemotherapy were eligible in this interim analysis. We analyzed associations between BMI and cardiotoxicity using multivariate logistic regression. At baseline, nearly 50% of the study population was overweight or obese. During a mean follow-up of 22 ± 2 months following treatment completion, cardiotoxicity occurred in 29 patients (3.2%). The obese group was more prone to cardiotoxicity than the normal-weight group (9/171 versus 8/466; p = 0.01). In multivariate analysis, obesity (odds ratio [OR] 3.02; 95% CI 1.10-8.25; p = 0.03) and administration of trastuzumab (OR 12.12; 95% CI 3.6-40.4; p < 0.001) were independently associated with cardiotoxicity. Selection bias and relatively short follow-up are potential limitations of this national multicenter observational cohort.ConclusionsIn BC patients, obesity appears to be associated with an important increase in risk-related cardiotoxicity (CANTO, ClinicalTrials.gov registry ID: NCT01993498).Trial registrationClinicalTrials.gov NCT01993498.
| S-EPMC6927582 | biostudies-literature
Project description:Anthracycline antibiotics (ANT), such as doxorubicin or daunorubicin, are a class of anticancer drugs that are widely used in oncology. Although highly effective in cancer therapy, their usefulness is greatly limited by their cardiotoxicity. Possible mechanisms of ANT cardiotoxicity include their conversion to secondary alcohol metabolites (i.e. doxorubicinol, daunorubicinol) catalyzed by carbonyl reductases (CBR) and aldo-keto reductases (AKR). These metabolites are suspected to be more cardiotoxic than their parent compounds. Moreover, overexpression of ANT-reducing enzymes (CBR and AKR) are found in many ANT-resistant cancers. The secondary metabolites show decreased cytotoxic properties and are more susceptible to ABC-mediated efflux than their parent compounds; thus, metabolite formation is considered one of the mechanisms of cancer resistance. Inhibitors of CBR and AKR were found to reduce the cardiotoxicity of ANT and the resistance of cancer cells, and therefore are being investigated as prospective cardioprotective and chemosensitizing drug candidates. In this review, the significance of a two-electron reduction of ANT, including daunorubicin, epirubicin, idarubicin, valrubicin, amrubicin, aclarubicin, and especially doxorubicin, is described with respect to toxicity and efficacy of therapy. Additionally, CBR and AKR inhibitors, including monoHER, curcumin, (-)-epigallocatechin gallate, resveratrol, berberine or pixantrone, and their modulating effect on the activity of ANT is characterized and discussed as potential mechanism of action for novel therapeutics in cancer treatment.
| S-EPMC5418329 | biostudies-literature
Project description:(1) The anticancer anthracycline doxorubicin (DOX) causes cardiomyopathy upon chronic administration. There is controversy about whether DOX acts directly or after conversion to its secondary alcohol metabolite DOXol. Here, the role of secondary alcohol metabolites was evaluated by treating rats with cumulative doses of DOX or analogues--like epirubicin (EPI) and the novel disaccharide anthracycline MEN 10755--which were previously shown to form less alcohol metabolites than DOX when assessed in vitro. (2) DOX induced electrocardiographic and haemodynamic alterations, like elongation of QalphaT or SalphaT intervals and suppression of isoprenaline-induced dP/dt increases, which developed in a time-dependent manner and were accompanied by cardiomegaly, histologic lesions and mortality. EPI caused less progressive or severe effects, whereas MEN 10755 caused essentially no effect. (3) DOX and EPI exhibited comparable levels of cardiac uptake, but EPI formed approximately 60% lower amounts of its alcohol metabolite EPIol at 4 and 13 weeks after treatment suspension (P<0.001 vs DOX). MEN 10755 exhibited the lowest levels of cardiac uptake; hence, it converted to its alcohol metabolite MEN 10755ol approximately 40% less efficiently than did EPI to EPIol at either 4 or 13 weeks. Cardiotoxicity did not correlate with myocardial levels of DOX or EPI or MEN 10755, but correlated with those of DOXol or EPIol or MEN 10755ol (P=0.008, 0.029 and 0.017, respectively). (4) DOX and EPI inactivated cytoplasmic aconitase, an enzyme containing an Fe-S cluster liable to disassembly induced by anthracycline secondary alcohol metabolites. DOX caused greater inactivation of aconitase than EPI, a finding consistent with the higher formation of DOXol vs EPIol. MEN 10755 did not inactivate aconitase, which was because of both reduced formation and impaired reactivity of MEN 10755ol toward the Fe-S cluster. Aconitase inactivation correlated (P<0.01) with the different levels of cardiotoxicity induced by DOX or EPI or MEN 10755. (5) These results show that (i) secondary alcohol metabolites are important determinants of anthracycline-induced cardiotoxicity, and (ii) MEN 10755 is less cardiotoxic than DOX or EPI, a behaviour attributable to impaired formation and reactivity of its alcohol metabolite.
| S-EPMC1573869 | biostudies-other
Project description:Validation of associations for SNPs in RAC2, NCF4 and SLC28A3, identification of a novel association with a TOP2B SNP and screening 23 SNPs putatively relevant to anthracycline-induced cardiotoxicity.A total of 166 breast cancer patients treated with doxorubicin underwent echocardiogram, including 19 cases with systolic dysfunction (ejection fraction <55%) and 147 controls. Four high priority SNPs were tested in the primary analysis, with appropriate statistical correction, and 23 additional SNPs were screened in an uncorrected secondary analysis.Previously reported associations for RAC2, NCF4 and SLC28A3 could not be validated and a novel association with TOP2B was not discovered in this cohort (all p > 0.05), likely due to inadequate power. Two SNPs were identified in the uncorrected secondary analysis including a protective SNP in ABCB1 (3435C>T, p = 0.049) and a risk allele in CBR3 (V244M, p = 0.012).The associations reported in prior publications and those discovered in this secondary analysis require further replication in independent cohorts.
| S-EPMC5558515 | biostudies-literature
Project description:BackgroundAnthracyclines are among the most effective chemotherapeutic agents in the treatment of numerous malignancies. Unfortunately, their use is limited by a dose-dependent cardiotoxicity. In an effort to prevent this cardiotoxicity, different cardioprotective agents have been studied.ObjectivesThe objective of this review was to assess the efficacy of different cardioprotective agents in preventing heart damage in cancer patients treated with anthracyclines.Search strategyWe searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 10), MEDLINE (1966 to November 2010) and EMBASE (1980 to November 2010) databases. In addition, we handsearched reference lists, conference proceedings of the International Society of Paediatric Oncology (SIOP) and American Society of Clinical Oncology (ASCO) meetings (1998 to 2010) and ongoing trials registers.Selection criteriaRandomised controlled trials (RCTs) in which any cardioprotective agent was compared to no additional therapy or placebo in cancer patients (children and adults) receiving anthracyclines.Data collection and analysisTwo review authors independently performed the study selection, risk of bias assessment and data extraction including adverse effects.Main resultsWe identified RCTs for the eight cardioprotective agents N-acetylcysteine, phenethylamines, coenzyme Q10, a combination of vitamins E and C and N-acetylcysteine, L-carnitine, carvedilol, amifostine and dexrazoxane (mostly for adults with advanced breast cancer). All studies had methodological limitations and for the first seven agents there were too few studies to allow pooling of results. None of the individual studies showed a cardioprotective effect. The 10 included studies on dexrazoxane enrolled 1619 patients. The meta-analysis for dexrazoxane showed a statistically significant benefit in favour of dexrazoxane for the occurrence of heart failure (risk ratio (RR) 0.29, 95% CI 0.20 to 0.41). No evidence was found for a difference in response rate or survival between the dexrazoxane and control groups. The results for adverse effects were ambiguous. No significant difference in the occurrence of secondary malignancies was identified.Authors' conclusionsNo definitive conclusions can be made about the efficacy of cardioprotective agents for which pooling of results was impossible. Dexrazoxane prevents heart damage and no evidence for a difference in response rate or survival between the dexrazoxane and control groups was identified. The evidence available did not allow us to reach any definite conclusions about adverse effects. We conclude that if the risk of cardiac damage is expected to be high, it might be justified to use dexrazoxane in patients with cancer treated with anthracyclines. However, clinicians should weigh the cardioprotective effect of dexrazoxane against the possible risk of adverse effects for each individual patient.
| S-EPMC6457676 | biostudies-literature
Project description:PURPOSE: Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant TOP trial, in which patients with estrogen receptor (ER)-negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase IIα (TOP2A) and to develop a gene expression signature to identify those patients who do not benefit from anthracyclines. METHODS: The TOP trial included 149 patients, of which 141 were evaluable for response prediction analyses. The primary endpoint was pathological complete response (pCR). TOP2A and gene expression profiles were evaluated using pre-epirubicin biopsies. Gene expression data from ER-negative samples of the EORTC 10994/BIG 00-01 and MDACC 2003-0321 neoadjuvant trials were used for validation purposes. RESULTS: A pCR was obtained in 14% of the evaluable TOP patients. TOP2A amplification, but not protein overexpression, was significantly associated with pCR (p=0.001 and 0.22). We developed an “anthracycline-based score (A-Score)” that combines three signatures: a TOP2A gene signature and two previously published signatures related to tumor invasion and immune response. The A-Score was characterized by a high negative predictive value (NPV=0.98 [95% CI: 0.90-1.00]) overall, and in the HER2-negative and HER2-positive subpopulations. Its performance was independently confirmed in the anthracycline-based (FAC/FEC) arms of the two validation trials (BIG 00-01: 0.80 [0.61-0.92] and MDACC 2003-0321: 1.00 [0.80-1.00]). CONCLUSION: Given its high NPV, the A-Score could become, if further validated, a useful clinical tool to identify those patients who do not benefit from anthracyclines and could therefore be spared the non-negligible side effects.
2010-01-26 | GSE16446 | GEO
Project description:The use of tubulin binders (TBs) in oncology indications often is associated with cardiotoxicity, the mechanism of which has not been elucidated. We observed that a single administration of TBs to rats caused an increase in the number of mitotic figures in the myocardial interstitium after 24 hours. We therefore hypothesized that interstitial cells are the primary target of TBs. To test this hypothesis, we evaluated the acute effects of a single intravenous administration of 3 reference TBs, colchicine (0.2 and 2 mg/kg), vinblastine (0.5 and 3 mg/kg), and vincristine (0.1 and 1 mg/kg) 6 and 24 hours after dosing. Mitotic arrest was identified at 24 hours in all high-dose groups based on an increase in the number of mitotic figures in the interstitium coupled with a dramatic decrease in the number of Ki67-positive interstitial cells. Analysis of the myocardial transcriptomic data further supported G2/M cell cycle arrest 6 hours after dosing with the high-dose groups of all 3 compounds. Apoptotic figures and an increase in the number of cleaved caspase 3-positive cells were identified at 6 and 24 hours at the highest dose of each compound almost exclusively in interstitial cells; a few cardiomyocytes were affected as well. Transcriptomic data further suggested that some of the affected interstitial cells were endothelial cells based on the up-regulation of genes typically associated with vascular damage and down-regulation of Endothelial Cell-Specific Molecule 1 and Apelin. Taken together, these data identify endothelial cells of the myocardium as the primary target of the cardiotoxicity of TBs and identify cell cycle arrest as the mechanism of this toxicity. Gene expression was profiled in the myocardium of rats at 6 and 24 hr after a single dose of colchicine, vinblastine or vincristine.
2010-01-01 | E-GEOD-19290 | biostudies-arrayexpress
Project description:Double-stranded sections of mRNA are often inviting sites of interaction for a wide variety of proteins and small molecules. Interactions at these sites can serve to regulate, or disrupt, the homeostasis of the encoded protein products. Such ligand target sites exist as hairpin-loop structures in the mRNAs of several of the proteins involved in iron homeostasis, including ferritin heavy and light chains, and are known as iron responsive elements (IREs). These IREs serve as the main control mechanism for iron metabolism in the cell via their interaction with the iron regulatory proteins (IRPs). Disruption of the IRE/IRP interaction could greatly affect iron metabolism. Here, we report that anthracyclines, a class of clinically useful chemotherapeutic drugs that includes doxorubicin and daunorubicin, specifically interact with the IREs of ferritin heavy and light chains. We characterized this interaction through UV melting, fluorescence quenching and drug-RNA footprinting. Results from footprinting experiments with wild-type and mutant IREs indicate that anthracyclines preferentially bind within the UG wobble pairs flanking an asymmetrically bulged C-residue, a conserved base that is essential for IRE-IRP interaction. Additionally, drug-RNA affinities (apparent K(d)s) in the high nanomolar range were calculated from fluorescence quenching experiments, while UV melting studies revealed shifts in melting temperature (DeltaT(m)) as large as 10 degrees C. This anthracycline-IRE interaction may contribute to the aberration of intracellular iron homeostasis that results from anthracycline exposure.
| S-EPMC2588532 | biostudies-literature