Search Results (346)

Doxorubicin, a commonly prescribed chemotherapeutic drug in clinical practice, is associated with severe cardiotoxicity that restricts its long-term use in cancer treatment. Recent studies have highlighted the critical roles of non-coding RNAs (ncRNAs) in the regulation of doxorubicin-induced cardiotoxicity (DIC). Notably, ncRNAs, including microRNAs, long non-coding RNAs, and circular RNAs, display critical functions in various DIC-associated cellular processes, such as cell death, oxidative stress, and mitochondrial dysfunction, all of which contribute to the pathophysiology of DIC. Accumulated evidence indicates that ncRNAs regulate gene expression by interacting with DNAs, RNAs, proteins, and lipids, presenting a potential avenue to alleviate the adverse effects of doxorubicin on hearts. This review discusses the emerging research progress focusing on the molecular mechanisms by which ncRNAs regulate DIC. Understanding the complicated and essential roles of ncRNAs in DIC could thus pave the way for developing novel cardioprotective strategies. Full article

Purpose: Doxorubicin (DOX) is a broad-spectrum anti-tumor anthracycline drug. However, its clinical application is greatly limited due to the side effect of cardiotoxicity. Caffeic acid phenethyl ester (CAPE) is one of the major biologically active compounds isolated from propolis, which is effective in the treatment of cardiovascular diseases. The purpose of this study aimed to explore the possible mechanism of CAPE’s protective effect on DOX-induced cardiotoxicity (DIC). Methods: In vivo, a DIC model was established by the intraperitoneal injection of 3 mg/kg DOX. The cardiac function of mice was monitored by electrocardiograms. Histopathological changes in myocardial tissue were detected by H&E staining. Serum samples were tested for the level of markers of myocardial injury. In vitro, transmission electron microscopy was used to assess the mitochondrial damage. Oxidative stress was measured by flow cytometry and mitochondrial respiration analysis. Necroptosis pathway changes were detected by Western blotting. Furthermore, the overexpression plasmid of a key necroptosis gene, necroptosis inhibitor or ROS inducer/inhibitor was applied to H9c2 and AC16 cells to explore whether CAPE exerted a protective effect against DIC through the cross-talk mediated by ROS and MLKL. Results: CAPE could improve the cardiac function and protect against myocardial tissue. CAPE pre-administration treatment attenuated the DOX-induced generation of ROS, protected mitochondrial functions and inhibited necroptosis. Moreover, there was cross-talk between the ROS and necroptosis. CAPE could protect against DIC by inhibiting the ROS-MLKL signaling that regulated the cross-talk. Conclusions: CAPE alleviated the oxidative stress and necroptosis of DIC, indicating that the cross-talk mediated by ROS-MLKL signaling may be a potential therapeutic mechanism for clinical DIC. Full article

Background: Depression is one of the leading causes of disability worldwide, with a significant impact on individuals’ quality of life. The use of antidepressants is fundamental in the treatment of this condition; however, it is essential to recognize that the use of these drugs can be associated with adverse effects, including cardiotoxicity. Methods: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a literature search was conducted of the PubMed/Medline, Scopus, and Cochrane databases. Twenty studies were included in the final quantitative analysis. The Joanna Briggs Institute critical appraisal tool was used to assess the risk of bias. Results: It is possible to highlight a correlation between intake of antidepressants and development of cardiotoxicity. Analysis of the selected studies allows for an understanding of the importance of a multidisciplinary approach for the protection of these patients. Conclusions: Management of antidepressant-induced cardiotoxicity requires a thorough understanding of the pathophysiological mechanisms involved and a critical evaluation of the various therapeutic strategies available to promote clinical practice. Full article

Cardiomyopathies are a heterogeneous group of heart muscle diseases that can lead to heart failure, arrhythmias, and sudden cardiac death. Traditional animal models and in vitro systems have limitations in replicating the complex pathology of human cardiomyopathies. Induced pluripotent stem cells (iPSCs) offer a transformative platform by enabling the generation of patient-specific cardiomyocytes, thus opening new avenues for disease modeling, drug discovery, and regenerative therapy. This process involves reprogramming somatic cells into iPSCs and subsequently differentiating them into functional cardiomyocytes, which can be characterized using techniques such as electrophysiology, contractility assays, and gene expression profiling. iPSC-derived cardiomyocyte (iPSC-CM) platforms are also being explored for drug screening and personalized medicine, including high-throughput testing for cardiotoxicity and the identification of patient-tailored therapies. While iPSC-CMs already serve as valuable models for understanding disease mechanisms and screening drugs, ongoing advances in maturation and bioengineering are bringing iPSC-based therapies closer to clinical application. Furthermore, the integration of multi-omics approaches and artificial intelligence (AI) is enhancing the predictive power of iPSC models. iPSC-based technologies are paving the way for a new era of personalized cardiology, with the potential to revolutionize the management of cardiomyopathies through patient-specific insights and regenerative strategies. Full article

Patients with active cancer and cancer survivors are at a markedly increased risk for developing cardiovascular comorbidities, including heart failure, coronary artery disease, and renal dysfunction, which are often compounded by the cardiotoxic effects of cancer therapies. This heightened cardiovascular vulnerability underscores the urgent need for effective, safe, and evidence-based cardioprotective strategies to reduce both cardiovascular morbidity and mortality. Sodium-glucose cotransporter 2 inhibitors (SGLT2is), a class of drugs originally developed for the treatment of type 2 diabetes, have demonstrated significant cardiovascular and renal benefits in high-risk populations, independent of glycemic control. Among the currently available SGLT2i, such as empagliflozin, canagliflozin, dapagliflozin, and sotagliflozin, there is growing evidence supporting their role in reducing major adverse cardiovascular events (MACEs), hospitalization for heart failure, and the progression of chronic kidney disease. Recent preclinical and clinical data suggest that SGLT2is exert cardioprotective effects through multiple mechanisms, including the modulation of inflammasome activity, specifically by reducing NLRP3 inflammasome activation and MyD88-dependent signaling, which are critical drivers of cardiac inflammation and fibrosis. Moreover, SGLT2is have been shown to enhance mitochondrial viability in cardiac cells, promoting improved cellular energy metabolism and function, thus mitigating cardiotoxicity. This narrative review critically evaluates the emerging evidence on the cardiorenal protective mechanisms of SGLT2is, with a particular focus on their potential role in cardio-oncology. We explore the common pathophysiological pathways between cardiovascular dysfunction and cancer, the molecular rationale for the use of SGLT2is in cancer patients, and the potential benefits in both primary and secondary prevention of cardiovascular toxicity related to oncological treatments. The aim is to propose a therapeutic paradigm utilizing SGLT2is to reduce cardiovascular mortality, MACE, and the burden of cardiotoxicity in high-risk oncology patients, fostering an integrated approach to cardio-oncology care. Full article

Approximately 5% to 8% of patients with Wilms tumour have bilateral disease. The prevalence of bilateral Wilms tumour (BWT) is higher in individuals with genetic predisposition syndromes than in those without. The goal of therapy is to preserve as much renal tissue as possible without compromising the overall oncological outcomes, utilising neoadjuvant chemotherapy followed by nephron sparing surgery (NSS) if possible. The Children’s Oncology Group (COG) in North America and the International Society of Paediatric Oncology (SIOP) in Europe have developed the main protocols for the treatment of BWT. Both protocols are similar: initial biopsies are not indicated, and they both recommend surgical resection at week 6 or no later than week 12. Chemotherapy includes the use of vincristine and actinomycin-D in both protocols, but the COG approach also includes the use of doxorubicin, which is a cardiotoxic drug with important long-term effects on the cardiac function of childhood cancer survivors. What doxorubicin adds to patients with BWT in terms of radiological tumour response, resectability, long-term renal function and overall survival, is still not very well described and it may be variable depending on the tumour biology. This article describes the current approach for BWT in North America and Europe, focusing on the potential effect that doxorubicin may have on patient outcomes. Full article

Breast cancer is the most common cancer in women worldwide. Anthracyclines (doxorubicin, epirubicin, daunorubicin, idarubicin) are among the most used drugs for the treatment of breast cancer. Unfortunately, anthracyclines cause cardiotoxicity, which is a limiting factor for its use, and the lifetime cumulative dose of anthracyclines is the major risk factor for cardiotoxicity. In our study, we focused on acute and subacute heart damage. One of the main factors is a genetic predisposition, which determines individual susceptibility to anthracycline cardiotoxicity. The main idea of this study was, for the first time, to evaluate drug metabolism-related genes as a risk factor for developing cardiovascular toxicity in breast cancer patients. The main objective of our study was to identify the impact of drug metabolism-related gene SNPs on the development of subclinical heart damage during and/or after doxorubicin-based chemotherapy in breast cancer patients. The data of 81 women with breast cancer treated with doxorubicin-based chemotherapy in an outpatient clinic were analyzed, and SNP RT-PCR tests were performed. The drug metabolism-related gene variants SULT2B1 rs10426377, UGT1A6 rs17863783, CBR1 rs9024, CBR3 rs1056892, NCF4 rs1883112, and CYBA rs1049255 did not reach a statistically important impact on ABCC in multivariate logistic regression analysis. However, we identified that NCF4 rs1883112 had a risk reduction tendency for ABCC (OR = 0.49, 95% CI 0.27–0.87, p = 0.015). Our findings suggest that some SNPs, such as NCF4 rs1883112, may be associated with a reduced risk of cardiotoxicity, while no variants in this study showed a statistically significant increased risk. Even though, NCF4 rs1883112 showed a risk reduction tendency, suggesting the potential for personalized risk stratification. We can conclude that multiple genes are involved in ABCC, with different impacts, and it is unlikely that there is a single driver gene in ABCC pathogenesis. Full article

Chemotherapy-related cardiotoxicity (CTRTOX) is a profound and common side effect of cancer-based therapy in a subset of patients. The underlying factors and the associated mechanisms contributing to severe toxicity of the heart among these patients remain unknown. While challenges remain in accessing human subjects and their ventricular cardiomyocytes (CMs), advancements in human induced pluripotent stem cell (hiPSC)-technology-based CM differentiation protocols over the past few decades have paved the path for iPSC-based models of human cardiac diseases. Here, we offer a detailed analysis of the underlying mechanisms of CTRTOX. We also discuss the recent advances in therapeutic strategies in different animal models and clinical trials. Furthermore, we explore the prospects of iPSC-based models for identifying novel functional targets and developing safer chemotherapy regimens for cancer patients that may be beneficial for developing personalized cardioprotectants and their application in clinical practice. Full article

Doxorubicin (DOX) is one of the most powerful chemotherapy drugs used to treat different kinds of cancer. However, its usage has been limited by typical side effects and drug resistance, particularly cardiotoxicity. According to studies, a more effective and promising method is to conjugate it or entrap it in biocompatible nanoparticles. Compared to free DOX and traditional formulations, nanoparticles using specific processes or techniques can improve drug stability, minimize premature release at untargeted locations, and lower systemic toxicity. This review explains how various nanocarriers target the tumor to improve therapeutic efficacy while reducing the negative effects of DOX. Full article

Background/Objectives: Urea transporters (UTs) play an important role in the urine-concentrating mechanism and have been regarded as a novel drug target for developing salt-sparing diuretics. Our previous studies found that diarylamides 1H and 25a are specific UT inhibitors and have oral diuretic activity. However, these compounds necessitate further optimization and comprehensive druggability studies. Methods: The optimal compound was identified through structural optimization. Experiments were conducted to investigate its UT inhibitory activity and evaluate its diuretic effect. Furthermore, disease models were utilized to assess the compound’s efficacy in treating hyponatremia. Pharmacokinetic studies were performed to examine its metabolic stability, and toxicity tests were conducted to evaluate its safety. Results: Based on the chemical structure of compound 25a, we synthesized a novel diarylamide compound, E3, by introducing a benzenesulfonamide group into its side chain. E3 exhibited dose-dependent inhibition of UT at the nanomolar level and demonstrated oral diuretic activity without causing electrolyte excretion disorders in both mice and rats. Experiments on UT-B^−/− and UT-A1^−/− mice indicated that E3 enhances the diuretic effect primarily by inhibiting UT-A1 more effectively than UT-B. Furthermore, E3 displayed good metabolic stability and favorable pharmacokinetic characteristics. E3 significantly ameliorated hyponatremia through diuresis in a rat model. Importantly, E3 did not induce acute oral toxicity, subacute oral toxicity, genotoxicity, or cardiotoxicity. Conclusions: Our study confirms that E3 exerts a diuretic effect by specifically inhibiting UTs and has good druggability, which offers potential for E3 to be developed into a new diuretic for the treatment of hyponatremia. Full article

The optimal descriptors generated by the CORAL software are studied as potential models of cardiotoxicity. Two significantly different cardiotoxicity databases are studied here. Database 1 contains 394 hERG inhibitors (pIC50) and external 200 substances that are potential drugs, which were used to confirm the predictive potential of the approach for Database 1. Database 2 contains cardiotoxicity data for 13864 different compounds in a format where active is denoted as 1 and inactive is denoted as 0. The same model-building algorithms were applied to all three databases using the Monte Carlo method and Las Vegas algorithm. The latter was used to rationally distribute the available data into training and validation sets. The Monte Carlo optimization for the correlation weights of different molecular features extracted from SMILES was improved by including the conformity coefficient of the correlation prediction (CCCP). This improvement provided greater predictive potential in the considered models. Full article

Background: GLP1 receptor agonists (GLP1-RAs) have become a central component in the treatment of type 2 diabetes mellitus (T2DM) and are gaining prominence in the cardiovascular field. Semaglutide and other GLP1-RA molecules possess cardioprotective properties. Cardiotoxicity, a term used to refer to cardiovascular disease caused by anticancer treatment, is a collection of common and severe conditions. Its pharmacological prevention or mitigation is a clinical unmet need as options are few and limited to some specific clinical settings. GLP1-RAs have a promising pharmacological profile given their activity on a number of pathophysiological targets and signaling pathways including oxidative stress, autophagy, and STAT3 activation. Interestingly, abnormalities in some of the GLP-1-modulated pathways have been linked to cardiotoxicity. This scoping review aims to map the extent and assess the main characteristics of research on the role of GLP1-RAs in the prevention and/or mitigation of anticancer-related cardiotoxicity. Methods: The selection process led to the inclusion of thirteen studies chosen from reports retrieved through the search string: (“semaglutide” OR “exenatide” OR “liraglutide” OR “dulaglutide” OR “tirzepatide” OR “GLP1 receptor agonist” OR “GLP1RA” OR “GLP1-RA” OR “GLP1” OR “Glucagon-like Peptide-1 Agonists”) AND (“cardioncology” OR “cardiotoxicity” OR “chemotherapy” OR “anti-cancer treatment” OR “anti-cancer therapy”). The study complied with the PRISMA guidelines on scoping reviews. Results: Two studies were clinical and conducted on registries, eight used animal models, two were conducted on cell cultures, and one was conducted on both animal models and cell cultures. Evidence in favor of cardioprotection and a number of putative mechanisms emerged. Conclusions: Evidence on GLP1-RAs’ effect on cardiotoxicity is limited in both quantity and quality and suffers from poor study standardization. However, most included studies documented a rigorously defined cardioprotective effect and demonstrated changes in several pathophysiologically relevant targets and pathways, including NF-κB, IL-6, reactive oxygen species, and caspase-3. Further clinical studies are warranted. Full article

Cancer medications can cause cardiac issues, which are difficult to treat in oncologic patients because of the risk of complications. In some cases, this may significantly impact their well-being and treatment outcomes. Overall, these complications fall under the term “drug induced cardiotoxicity”, mainly due to chemotherapy drugs being specifically toxic to the heart, causing a decrease in the heart’s capacity to pump blood efficiently and leading to a reduction in the left ventricular ejection fraction (LVEF), and subsequently possibly leading to heart failure. Anthracyclines, alkylating agents, and targeted therapies for cancer hold the potential of causing harmful effects on the heart. The incidence of heart-related issues varies from patient to patient and depends on multiple factors, including the type of medication, dosage, duration of the treatment, and pre-existing heart conditions. The underlying mechanism leading to oncologic-drug-induced cardiovascular harmful effects is quite complex. One particular group of drugs, called anthracyclines, have garnered attention due to their impact on oxidative stress and their ability to cause direct harm to heart muscle cells. Reactive oxygen species (ROS) cause harm by inducing damage and programmed cell death in heart cells. Conventional biomarkers alone can only indicate some degree of damage that has already occurred and, therefore, early detection is key. Novel methods like genetic profiling are being developed to detect individuals at risk, prior to the onset of clinical symptoms. Key management strategies—including early detection, personalized medicine approaches, and the use of novel biomarkers—play a crucial role in mitigating cardiotoxicity and improving patient outcomes. Identification of generated genetic alterations and the association to an increased likelihood of cardiotoxicity will allow treatment in a more personalized approach, aiming at decreasing rates of cardiac events while maintaining high oncological efficacy. Oncology drug-induced cardiotoxicity is managed through a combination of preventive strategies and therapeutic interventions from the union of cardiac and oncological knowledge. Full article

Doxorubicin (DOX) is used for the treatment of various malignancies, including leukemias, lymphomas, sarcomas, and bladder, breast, and gynecological cancers in adults, adolescents, and children. However, DOX causes severe side effects in patients, such as cardiotoxicity, which encompasses heart failure, arrhythmia, and myocardial infarction. DOX-induced cardiotoxicity (DIC) is based on the combination of nuclear-mediated cardiomyocyte death and mitochondrial-mediated death. Oxidative stress, altered autophagy, inflammation, and apoptosis/ferroptosis represent the main pathogenetic mechanisms responsible for DIC. In addition, in vitro and in vivo models of DIC sirtuins (SIRT), and especially, SIRT 1 are reduced, and this event contributes to cardiac damage. In fact, SIRT 1 inhibits reactive oxygen species and NF-kB activation, thus improving myocardial oxidative stress and cardiac remodeling. Therefore, the recovery of SIRT 1 during DIC may represent a therapeutic strategy to limit DIC progression. Natural products, i.e., polyphenols, as well as nano formulations of DOX and iron chelators, are other potential compounds experimented with in models of DIC. At present, few clinical trials are available to confirm the efficacy of these products in DIC. The aim of this review is the description of the pathophysiology of DIC as well as potential drug targets to alleviate DIC. Full article

Objectives: There is growing concern over tyrosine kinase inhibitor (TKI)-induced cardiotoxicity, particularly regarding left ventricular dysfunction and heart failure in clinical treatment. These adverse effects often lead to treatment discontinuation, severely impacting patient outcomes. Therefore, there is an urgent need for more precise risk assessment methods. This study aimed to assess the cardiotoxicity of TKIs, refine in vitro to in vivo extrapolation (IVIVE) methodologies to improve predictive accuracy, and identify critical in vitro parameters for assessment. Methods: By leveraging high-throughput cardiotoxicity screening with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), a mechanism-based toxicodynamic (TD) model for TKIs was constructed. A QSP-PK-TD model was developed by integrating pharmacokinetic (PK) and quantitative systems pharmacology (QSP) models. This model incorporates critical drug exposure factors, such as plasma protein binding, tissue–plasma partitioning, and drug distribution heterogeneity to enhance extrapolation accuracy. Results: The QSP-PK-TD model validated the reliability of IVIVE and identified the area under the curve of drug effects on mitochondrial membrane potential (AEMMP) and cardiomyocyte contractility (AEAAC) as key in vitro parameters for assessing TKI-induced cardiotoxicity. Incorporating critical drug exposure factors obviously improved qualitative and quantitative extrapolation accuracy. Conclusions: This study established a framework for predicting in vivo cardiotoxicity from in vitro parameters, enabling efficient translation of preclinical data into clinical risk assessment. These findings provide valuable insights for drug development and regulatory decision-making, offering a powerful tool for evaluating TKI-induced cardiotoxicity. Full article