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Rutin protects against pirarubicin-induced cardiotoxicity by adjusting microRNA-125b-1-3p-mediated JunD signaling pathway.
Mol Cell Biochem. 2020 Feb 03;:
Authors: Li Q, Qin M, Li T, Gu Z, Tan Q, Huang P, Ren L
Abstract
Pirarubicin (THP), an anthracycline drug, is widely used as a basic therapeutic agent for the treatment of carcinoma and lymphatic malignant tumor. However, it exerts irreversible cardiotoxicity in varying degrees. At present, dexrazoxane (DZR) is the only cardioprotective agent used to treat anthracycline drug-induced cardiotoxicity, but it may reduce the anticancer effect of anthracycline drugs, causing severe granulocytopenia and other adverse reactions. Therefore, it is necessary to discover more effective and less toxic drugs for the treatment of THP-induced cardiotoxicity. The present study aimed to investigate the effects and possible mechanisms of rutin (RUT) against THP-induced cardiomyocyte injury. An in vitro cardiomyocyte injury model of THP-treated murine immortalized cardiomyocytes (HL-1) was used in this study. The results showed that RUT markedly increased the viability of HL-1 cells through protection against THP-induced cardiomyocyte injury. Furthermore, RUT significantly inhibited myocardial oxidative insult by adjusting the levels of intracellular reactive oxygen species (ROS). Our data also indicated that RUT activated JunD signaling pathways, thereby affecting the expression levels of some apoptotic proteins by decreasing miR-125b-1-3p expression level. In addition, intracellular ROS level significantly increased in HL-1 cells treated with THP after miR-125b-1-3p mimic transfection, whereas the expression of JunD was downregulated and that of some apoptotic proteins was upregulated. However, this effect was markedly reversed by RUT. Therefore, we inferred that the protective effect of RUT on THP cardiotoxicity was achieved through regulation of the JunD gene by miR-125b-1-3p. This experiment revealed the protective effect of RUT on THP-induced cardiotoxicity at the non-coding RNA level and provided a theoretical foundation for the application of RUT as a protective agent against THP cardiotoxicity.
PMID: 32016695 [PubMed - as supplied by publisher]
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Classification, prevalence, and outcomes of anticancer therapy-induced cardiotoxicity: the CARDIOTOX registry.
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Classification, prevalence, and outcomes of anticancer therapy-induced cardiotoxicity: the CARDIOTOX registry.
Eur Heart J. 2020 Feb 04;:
Authors: López-Sendón J, Álvarez-Ortega C, Zamora Auñon P, Buño Soto A, Lyon AR, Farmakis D, Cardinale D, Canales Albendea M, Feliu Batlle J, Rodríguez Rodríguez I, Rodríguez Fraga O, Albaladejo A, Mediavilla G, González-Juanatey JR, Martínez Monzonis A, Gómez Prieto P, González-Costello J, Serrano Antolín JM, Cadenas Chamorro R, López Fernández T
Abstract
AIM: Cardiotoxicity (CTox) is a major side effect of cancer therapies, but uniform diagnostic criteria to guide clinical and research practices are lacking.
METHODS AND RESULTS: We prospectively studied 865 patients, aged 54.7 ± 13.9; 16.3% men, scheduled for anticancer therapy related with moderate/high CTox risk. Four groups of progressive myocardial damage/dysfunction were considered according to current guidelines: normal, normal biomarkers (high-sensitivity troponin T and N-terminal natriuretic pro-peptide), and left ventricular (LV) function; mild, abnormal biomarkers, and/or LV dysfunction (LVD) maintaining an LV ejection fraction (LVEF) ≥50%; moderate, LVD with LVEF 40-49%; and severe, LVD with LVEF ≤40% or symptomatic heart failure. Cardiotoxicity was defined as new or worsening of myocardial damage/ventricular function from baseline during follow-up. Patients were followed for a median of 24 months. Cardiotoxicity was identified in 37.5% patients during follow-up [95% confidence interval (CI) 34.22-40.8%], 31.6% with mild, 2.8% moderate, and 3.1% with severe myocardial damage/dysfunction. The mortality rate in the severe CTox group was 22.9 deaths per 100 patients-year vs. 2.3 deaths per 100 patients-year in the rest of groups, hazard ratio of 10.2 (95% CI 5.5-19.2) (P
CONCLUSIONS: The majority of patients present objective data of myocardial injury/dysfunction during or after cancer therapy. Nevertheless, severe CTox, with a strong prognostic relationship, was comparatively rare. This should be reflected in protocols for clinical and research practices.
PMID: 32016393 [PubMed - as supplied by publisher]
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Synthetic routes to nanoconjugates of anthracyclines.
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Synthetic routes to nanoconjugates of anthracyclines.
Bioorg Chem. 2020 Jan 25;96:103617
Authors: Piorecka K, Smith D, Kurjata J, Stanczyk M, Stanczyk WA
Abstract
Anthracyclines (Anth) are widely used in the treatment of various types of cancer. Unfortunately, they exhibit serious adverse effects, such as hematopoietic depression and cardiotoxicity, leading to heart failure. In this review, we focus on recently developed conjugates of anthracyclines with a range of nanocarriers, such as polymers, peptides, DNA or inorganic systems. Manipulation of the composition, size and shape of chemical entities at the nanometer scale makes possible the design and development of a range of prodrugs. In this review we concentrate on synthetic chemistry in the long process leading to the introduction of novel therapeutic products.
PMID: 32014639 [PubMed - as supplied by publisher]
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Bioinformatic analysis of peripheral blood miRNA of breast cancer patients in relation with anthracycline cardiotoxicity.
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Bioinformatic analysis of peripheral blood miRNA of breast cancer patients in relation with anthracycline cardiotoxicity.
BMC Cardiovasc Disord. 2020 Feb 03;20(1):43
Authors: Yadi W, Shurui C, Tong Z, Suxian C, Qing T, Dongning H
Abstract
BACKGROUND: The current diagnostic methods and treatments still fail to lower the incidence of anthracycline-induced cardiotoxicity effectively. In this study, we aimed to (1) analyze the cardiotoxicity-related genes after breast cancer chemotherapy in gene expression database and (2) carry out bioinformatic analysis to identify cardiotoxicity-related abnormal expressions, the biomarkers of such abnormal expressions, and the key regulatory pathways after breast cancer chemotherapy.
METHODS: Cardiotoxicity-related gene expression data (GSE40447) after breast cancer chemotherapy was acquired from the Gene Expression Omnibus (GEO) database. The biomarker expression data of women with chemotherapy-induced cardiotoxicity (group A), chemotherapy history but no cardiotoxicity (group B), and confirmatory diagnosis of breast cancer but normal ejection fraction before chemotherapy (group C) were analyzed to obtain the mRNA with differential expressions and predict the micro RNAs (miRNAs) regulating the differential expressions. The miRanda formula and functional enrichment analysis were used to screen abnormal miRNAs. Then, the Gene Ontology (GO) analysis was adapted to further screen the miRNAs related to cardiotoxicity after breast cancer chemotherapy.
RESULT: The data of differential analysis of biomarker expression of groups A, B, and C using the GSE40447-related gene expression profile database showed that there were 30 intersection genes. The differentially expressed mRNAs were predicted using the miRanda and Target Scan software, and a total of 2978 miRNAs were obtained by taking the intersections. Further, the GO analysis and targeted regulatory relationship between miRNA and target genes were used to establish miRNA-gene interaction network to screen and obtain seven cardiotoxicity-related miRNAs with relatively high centrality, including hsa-miR-4638-3p, hsa-miR-5096, hsa-miR-4763-5p, hsa-miR-1273 g-3p, hsa-miR6192, hsa-miR-4726-5p and hsa-miR-1273a. Among them, hsa-miR-4638-3p and hsa-miR-1273 g-3p had the highest centrality. The PCR verification results were consistent with those of the chip data. There are differentially expressed miRNAs in the peripheral blood of breast cancer patients with anthracycline cardiotoxicity. Among them, hsa-miR-4638-3p and hsa-miR-1273 g-3p are closely associated with the onset of anthracycline cardiotoxicity in patients with breast cancer. The signaling pathway is mainly concentrated in TGF-β signaling pathway and adhesion signaling pathway.
CONCLUSIONS: Changes in expression of hsa-miR-4638-3p and hsa-miR-1273 g-3p may contribute to the detection of anthracyclines induced cardiac toxicity, and their potential function may be related to TGF-β signaling pathway and adhesion signaling pathway.
PMID: 32013934 [PubMed - in process]
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A tumor-targeted, intracellular activatable and theranostic nanodiamond drug platform for strongly enhanced in vivo antitumor therapy.
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A tumor-targeted, intracellular activatable and theranostic nanodiamond drug platform for strongly enhanced in vivo antitumor therapy.
J Mater Chem B. 2020 Feb 03;:
Authors: Du X, Li L, Wei S, Wang S, Li Y
Abstract
Enhancing tumor homing and improving the efficacy of drugs are urgent needs for cancer treatment. Herein a novel targeted, intracellularly activatable fluorescence and cytotoxicity nanodiamond (ND) drug system (ND-PEG-HYD-FA/DOX, NPHF/D) was successfully prepared based on doxorubicin (DOX) and folate (FA) covalently bound to PEGylated NDs, in which the DOX was covalently coupled via an intracellularly hydrolyzable hydrazone bond that was stable in the physiological environment to ensure minimal drug release in circulation. Cell uptake studies demonstrated the selective internalization of NPHF/D by folate receptor (FR) mediated endocytosis in the order MCF-7 > HeLa > HepG2 ≫ CHO, using confocal laser scanning microscopy (CLSM) and flow cytometry. Interestingly, the DOX fluorescence of NPHF/D was significantly quenched, while the fluorescence recovery and cytotoxicity took place by low pH regulation in intracellular lysosomes, which made NPHF/D act as a fluorescence OFF-ON messenger for activatable imaging and cancer therapy. Of note, NPHF/D significantly inhibited the growth of tumors. Simultaneously, it was demonstrated that the introduction of FA and the cleavability of the hydrazone greatly enhanced the therapeutic performance of NPHF/D. In addition, toxicity studies in mice verified that the composites were devoid of any detected hepatotoxicity, cardiotoxicity, and nephrotoxicity using histopathology and blood biochemistry studies. Our work provides a novel strategy for cancer therapy, using ND-conjugated cancer drugs, and the exploration of theranostic drug-delivery systems.
PMID: 32011619 [PubMed - as supplied by publisher]
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Involvement of neurotrophic signaling in doxorubicin-induced cardiotoxicity.
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Involvement of neurotrophic signaling in doxorubicin-induced cardiotoxicity.
Exp Ther Med. 2020 Feb;19(2):1129-1135
Authors: Liao D, Zhang C, Liu N, Cao L, Wang C, Feng Q, Yao D, Long M, Jiang P
Abstract
Dose dependent cardiotoxicity is the primary side effect of doxorubicin (DOX), but the underlying molecular mechanisms remain unclear. An increasing amount of evidence has demonstrated that neurotrophic signaling plays a pivotal role in both neurons and the heart, but the biological association between neurotrophic signaling and DOX-induced cardiotoxicity remains unknown. The present study determined the level of neurotrophins and their receptors in the heart of rats following DOX administration. DOX was administered 7 times at a dose of 2.5 mg/kg once every 2 days via intraperitoneal injection. The present study revealed that cardiac injury parameters, such as creatine kinase (CK), creatine kinase-myocardial bound, lactate dehydrogenase, troponin T and aspartate transaminase in serum were significantly increased in the DOX group. Both the gene and protein expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the heart were markedly decreased following DOX treatment. Notably, the protein level of BDNF in the serum was inhibited in DOX-treated rats, whereas DOX induced a significant increase in the protein level of NGF in the serum. DOX induced a significant decrease in the level of tropomyosin-associated kinase A (TrkA) and the ratio of pTrkA/TrkA and pTrkB/TrkB. Furthermore, the administration of DOX suppressed downstream protein kinase B and extracellular signal regulated kinase phosphorylation. The present study first demonstrated that BDNF/TrkB signaling and NGF/TrkA signaling were altered by DOX, which indicated that neurotrophic signaling was involved in DOX-induced cardiotoxicity.
PMID: 32010279 [PubMed]
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Chemotherapy-Induced Cardiotoxicity in Adolescent After Heart Transplant: Do Not Forget the Right Ventricle.
//www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--production.springer.de-OnlineResources-Logos-springerlink.gif Related Articles
Chemotherapy-Induced Cardiotoxicity in Adolescent After Heart Transplant: Do Not Forget the Right Ventricle.
Pediatr Cardiol. 2019 Dec;40(8):1756-1758
Authors: Salas-Mera D, Deiros-Bronte L, Uceda-Galiano Á, Mozo-Del Castillo Y, García-Guereta L, Gutiérrez-Larraya F
Abstract
The evaluation of oncologic patients at risk of chemotherapy-induced cardiotoxicity usually focuses on left ventricular function. However, recent studies have demonstrated that right ventricle impairment often coexists (and in some cases precedes) left-side affectation. We present the case of a 19-year-old heart transplant recipient who developed severe right ventricular dysfunction secondary to treatment of an abdominal lymphoma.
PMID: 31367951 [PubMed - indexed for MEDLINE]
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Connections Between Clonal Hematopoiesis, Cardiovascular Disease, and Cancer: A Review.
//www.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--jamanetwork.com-images-JAMA_cardio_linkout.gif Related Articles
Connections Between Clonal Hematopoiesis, Cardiovascular Disease, and Cancer: A Review.
JAMA Cardiol. 2019 04 01;4(4):380-387
Authors: Calvillo-Argüelles O, Jaiswal S, Shlush LI, Moslehi JJ, Schimmer A, Barac A, Thavendiranathan P
Abstract
Importance: Clonal hematopoiesis (CH) has been recently described as a novel driver for cancer and cardiovascular disease (CVD). Clonal hematopoiesis is a common, age-associated disorder marked by expansion of hematopoietic clones carrying recurrent somatic mutations. Current literature suggests that patients with CH have a higher risk of subsequent hematological malignant conditions and mortality attributable to excess CVD. This review discusses the association of cancer with CVD with CH as a potential unifying factor.
Observations: The prevalence of CH varies based on the sequencing depth, diagnostic criteria, and patient age and ranges from less than 1% in those younger than 40 years to more than 15% to 20% in those 90 years and older. Clonal hematopoiesis is associated with a 0.5% to 1.0% absolute annual risk of hematological malignant condition and a 2-fold to 4-fold higher risk of coronary artery disease, stroke, and CVD deaths, independent of traditional cardiovascular risk factors. In fact, CH appears to have a relative risk similar to that of traditional cardiovascular risk factors for CVD. Experimental studies suggest that the link between CVD and CH is causal, with inflammation as 1 potential mechanism. There may be also a link between CH and CVD in survivors of cancer; however, data to support this association are currently limited.
Conclusions and Relevance: Clonal hematopoiesis represents a premalignant state, with carriers having an increased risk of hematological malignant conditions. Although most carriers will not develop a malignant condition, CH confers an increased risk of CVD, possibly via inflammation. Clonal hematopoiesis may also contribute to CVD in survivors of cancer, although this hypothesis requires validation. Clinically, as advanced sequencing techniques become available, CH may pave the way for precision medicine in the field of cardio-oncology.
PMID: 30865214 [PubMed - indexed for MEDLINE]
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