Adriamycin-induced Cardiotoxicity Research Articles

Identification of Dalbergiae Odoriferae Lignum active ingredients and potential mechanisms in the treatment of adriamycin-induced cardiotoxicity based on network pharmacology and experimental verification.

The purpose of this study is to investigate the ingredients and mechanisms through which Dalbergiae Odoriferae Lignum (DOL) reduces adriamycin-induced cardiotoxicity. DOL's ingredients and drug targets were acquired from Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP), and adriamycin-induced cardiotoxicity disease targets were gathered from GeneCards and National Center for Biotechnology Information (NCBI). The therapeutic targets of DOL against adriamycin-induced cardiotoxicity were identified by intersecting drug and disease targets. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) were conducted using R. Subsequently, core targets were determined and used for molecular docking with DOL ingredients. In vitro and in vivo experiments validated DOL's primary ingredients against adriamycin-induced cardiotoxicity efficacy. Western blot and immunohistochemistry verified its impact on target protein. After intersecting 530 drug targets and 51 disease targets, 19 therapeutic targets for DOL alleviated adriamycin-induced cardiotoxicity were received. Molecular docking demonstrated that DOL primary ingredient formononetin had a robust binding affinity for nitric oxide synthase 3 (NOS3). Experimental results showed that formononetin effectively mitigated adriamycin-induced cardiotoxicity. Additionally, western blot and immunohistochemistry showed that formononetin improved NOS3 expression. The network pharmacology and experimentation suggest that the primary ingredient of DOL, formononetin, may target NOS3 to act as a therapeutic agent for adriamycin-induced cardiotoxicity.

Adriamycin downregulates the expression of KLF4 in cardiomyocytes in vitro and contributes to impaired cardiac energy metabolism in Adriamycin-induced cardiomyopathy.

Adriamycin is a well-known anthracycline chemotherapeutic agent widely used in treating a variety of malignancies. However, Adriamycin's clinical use is limited due to its adverse side-effects, most importantly cardiomyopathy. Adriamycin-induced cardiotoxicity reportedly includes mitochondrial dysfunction. We hypothesize that modulation of KLF4, a key regulator of cardiac mitochondrial homeostasis might play a role in the development of Adriamycin-induced cardiomyopathy. Therefore, in the current work, we evaluated the interaction of Adriamycin with KLF4 and its subsequent downstream targets. Molecular docking revealed that Adriamycin interacts strongly with KLF4 at residues Thr 448, Arg 452, Ser 444 falls within C2H2 motif which is the active site. Quantitative real-time PCR also revealed that KLF4 is downregulated by Adriamycin in cardiomyocytes in vitro. The expression of KLF4 is downregulated in a dose-dependent manner, with a 0.12 ± 0.09-fold (p ≤ 0.05, n = 3) downregulation at a low dosage and 0.21 ± 0.02-fold (p ≤ 0.05, n = 3) downregulation at high dosage. Deficiency of KLF4 leads to an impairment of PPARγ that consequently supresses the proteins/enzymes involved in the fatty acid metabolism. Adriamycin-mediated suppression of KLF4 also affected the expression of PPARα in vitro. PPARα dysfunction is likely to cause defects in β-oxidation which ultimately results in impaired ATP synthesis. Cardiac cells are thus forced to switch over the substrate from free fatty acid to glucose. Moreover, Adriamycin elevates the expression of PPARβ due to downregulation of KLF4 leads to increased myocardial glucose utilization. Thus, a change in substrate preference affects the flexibility of metabolic network culminating in diminished energy production and other regulatory activities, altogether contributing to the development of cardiomyopathy. Thus, we conclude that the effect of Adriamycin on KLF4 disrupts mitochondrial homeostasis and lipid/glucose homeostasis resulting in a reduction of ATP synthesis which ultimately results in dilated cardiomyopathy.

Cardioprotective Mechanism and Active Compounds of Folium Ginkgo on Adriamycin-Induced Cardiotoxicity: A Network Pharmacology Study.

Objective To investigate the mechanism of Folium Ginkgo (FG) against adriamycin-induced cardiotoxicity (AIC) through a network pharmacology approach. Methods Active ingredients of FG were screened by TCMSP, and the targets of active ingredient were collected by Genclip3 and HERB databases. AIC-related target genes were predicted by Genecards, OMIM, and CTD databases. Protein-protein interaction (PPI) network was constructed by STRING platform and imported into Cytoscape software to construct the FG-active ingredients-targets-AIC network, and CytoNCA plug-in was used to analyze and identify the core target genes. The Metascape platform was used for transcription factor, GO and signaling pathway enrichment analysis. Results 27 active ingredients of FG and 1846 potential targets were obtained and 358 AIC target genes were retrieved. The intersection of FG and AIC targets resulted in 218 target genes involved in FG action. The top 5 active ingredients with most targets were quercetin, luteolin, kaempferol, isorhamnetin, and sesamin. After constructing the FG-active ingredients-targets-AIC network, CytoNCA analysis yielded 51 core targets, of which the top ranked target was STAT3. Ninety important transcription factors were enriched by transcription factor enrichment analysis, including RELA, TP53, NFKB1, SP1, JUN, STAT3, etc. The results of GO enrichment analysis showed that the effective active ingredient targets of FG were involved in apoptotic signaling, response to growth factor, cellular response to chemical stress, reactive oxygen species metabolic process, etc. The signaling pathway enrichment analysis showed that there were many signaling pathways involved in AIC, mainly including pathways in cancer, FOXO signaling pathway, AGE-RAGE signaling pathway in diabetic complications, signaling by interleukins, and PI3K-AKT signaling pathway,. Conclusions The study based on a network pharmacology approach demonstrates that the possible mechanisms of FG against AIC are the involvement of multicomponents, multitargets, and multipathways, and STAT3 may be a key target. Further experiments are needed to verify the results.

Protective effects and mechanisms of lycorine against adriamycin-induced cardiotoxicity

BackgroundAdriamycin (ADR), a high-efficiency, broad-spectrum anthraquinone chemotherapeutic agent, is currently used to treat various malignant tumors and can lead to cumulative, dose-dependent, and irreversible cardiotoxicity. Lycorine (LYC) is a benzyl phenethylamine alkaloid that exerts remarkable therapeutic effects on cancers and sepsis. PurposeHowever, researchers have not yet elucidated whether LYC exerts protective effects against cardiotoxicity induced by ADR and the possible molecular mechanisms. DesignThis study established ADR injury models in vitro and in vivo to explore the effects of LYC against cardiotoxicity induced by ADR. The effects of LYC on blood biochemical parameters, cardiac parameters and structure, ADR-related pathophysiological processes, and the SIRT1/PPARγ signal pathway in ADR-injured models, were analyzed using a series of experimental methods. ResultsLYC significantly improved survival rate, blood biochemical parameters (LDH, CK, and BUN), cardiac parameters (SV and CO), mitochondrial dysfunction, and ameliorated oxidative stress, apoptosis, and myocardial fibrosis in ADR-injured mice (p<0.05). Moreover, LYC obviously increased cell viability and reduced oxidative stress, apoptosis, and mitochondrial dysfunction in ADR-injured cells (p<0.05). Furthermore, this study confirmed that the protective effect of LYC on ADR-induced cardiotoxicitymight be mediated by the SIRT1/PPARγ signaling pathway. These results revealed that the beneficial role of LYC on cardiotoxicity induced by ADR were mediated via regulating SIRT1/PPARγ signaling for the first time. ConclusionThese discoveries may provide a theoretical basis for the exploitation of LYC as a potential cardioprotective drug candidate due to its multiple biological functions to reduce ADR-induced cardiotoxicity, but further preclinical and clinical studies are still needed.

Protective effects and mechanisms of psoralidin against adriamycin-induced cardiotoxicity

IntroductionAdriamycin (ADR) is an efficient and common broad-spectrum anticancer drug. However, the cumulative and dose-dependent toxicity induced by ADR severely limits its application in the clinic. Previous studies found that psoralidin (PSO) exhibits remarkable therapeutic effects against multiple cancers. ObjectivesThe aim of this study was to determine if PSO has beneficial effects on ADR-induced cardiotoxicity and to investigate the underlying mechanisms. MethodsADR-induced cardiotoxicity models were established in BALB/c mice and HL-1 cardiomyocytes. A series of experimental methods were used to evaluate the effects of PSO on cardiac function indicators, blood biochemical parameters, histopathology, oxidative stress, apoptosis, mitochondrial function, fibrosis, and SIRT1/PPARγ signaling. ResultsPSO significantly improved cardiac function indicators, blood biochemical parameters, and mitochondrial function and reduced the degree of myocardial fibrosis, oxidative stress, and apoptosis in ADR-injured mice. PSO significantly increased cell viability, inhibited the release of LDH, reduced oxidative stress and apoptosis, and improved mitochondrial function in ADR-injured HL-1 cells. Moreover, we also demonstrated there was cross-talk between SIRT1 and PPARγ, as shown by SIRT1 siRNA significantly decreasing the expression of PPARγ and GW9662 (a PPARγ antagonist), which remarkably reduced the expression of SIRT1. ConclusionIn summary, this study proved for the first time the beneficial effect of PSO on ADR-induced cardiotoxicity through activation of the SIRT1/PPARγ signaling pathway. Therefore, these findings may favor PSO as a potential cardioprotective drug candidate to alleviate ADR-induced cardiotoxicity in the clinic and improve the application of ADR in oncotherapy.

A new FGF1 variant protects against adriamycin-induced cardiotoxicity via modulating p53 activity

A cumulative and progressively developing cardiomyopathy induced by adriamycin (ADR)-based chemotherapy is a major obstacle for its clinical application. However, there is a lack of safe and effective method to protect against ADR-induced cardiotoxicity. Here, we found that mRNA and protein levels of FGF1 were decreased in ADR-treated mice, primary cardiomyocytes and H9c2 cells, suggesting the potential effect of FGF1 to protect against ADR-induced cardiotoxicity. Then, we showed that treatment with a FGF1 variant (FGF1ΔHBS) with reduced proliferative potency significantly prevented ADR-induced cardiac dysfunction as well as ADR-associated cardiac inflammation, fibrosis, and hypertrophy. The mechanistic study revealed that apoptosis and oxidative stress, the two vital pathological factors in ADR-induced cardiotoxicity, were largely alleviated by FGF1ΔHBS treatment. Furthermore, the inhibitory effects of FGF1ΔHBS on ADR-induced apoptosis and oxidative stress were regulated by decreasing p53 activity through upregulation of Sirt1-mediated p53 deacetylation and enhancement of murine double minute 2 (MDM2)-mediated p53 ubiquitination. Upregulation of p53 expression or cardiac specific-Sirt1 knockout (Sirt1-CKO) almost completely abolished FGF1ΔHBS-induced protective effects in cardiomyocytes. Based on these findings, we suggest that FGF1ΔHBS may be a potential therapeutic agent against ADR-induced cardiotoxicity.

Betanin and Allicin Ameliorate Adriamycin-Induced Cardiotoxicity in Rats by Ameliorating Cardiac Ischemia and Improving Antioxidant Efficiency

Aims: To investigate the protective effects of betanin and allicin against adriamycin (ADR)-induced cardiotoxicity.&#x0D; Study Design: Experimental animal model.&#x0D; Place and Duration of Study: King Abdul-Aziz University, Jeddah, Saudi Arabia; 10 days.&#x0D; Methodology: Adult female Wistar rats were allocated to the following groups (n = 10 per group): Control, received water, a standard diet for 10 days and i.p normal saline on day 8; ADR, intraperitoneal injection with 15 mg/kg ADR as a single dose on day 8; ADR+BE, betanin (20 mg/kg) administration followed by i.p. injection of ADR (15 mg/kg); ADR+ALL, allicin (20 mg/kg) administration followed by i.p. injection of ADR; and ADR+BE+ALL, equal volumes of betanin and allicin followed by ADR (15 mg/kg). Hemodynamic characteristics of the cardiovascular system and electrocardiography were evaluated. Blood samples were obtained to assess cardiac enzymes; cardiac homogenates were processed to analyze oxidative and antioxidant parameters and low-grade inflammatory indicators. Histopathological evaluation of heart tissues was also conducted.&#x0D; Results: Rats pre-administered betanin and allicin were protected from ADR-associated ischemia based on the significant (P &lt; .05) shortening of QT, QTC interval, QRS, and T peak Tend interval compared with the ADR group. Betanin and allicin pre-treatment significantly decreased the ADR-induced elevated serum creatine kinase-MB and lactate dehydrogenase levels. ADR-elevated cardiac oxidative parameters, along with the serum concentrations of the tumor necrosis factor-alpha and the cardiac transforming growth factor-beta, were significantly inhibited by betanin and allicin. Histopathological findings confirmed the biochemical results. Betanin and allicin reduced ADR-induced heart damage by inhibiting several pathways, including those of oxidative stress and inflammation.&#x0D; Conclusion: Betanin and allicin may be promising cardioprotective agents owing to their antioxidant and cytoprotective properties and could thus be used as adjuvant treatment for cancer therapy.

Cytoprotective and antioxidant effects of aged garlic extract against adriamycin-induced cardiotoxicity in adult male rats.

Adriamycin (ADR) efficacy in cancer chemotherapy is well-established. However, ADR-induced cardiotoxicity remains a significant challenge. Aged garlic extract (AGE) is a natural polyphenol with high antioxidant potential. This study was planned to determine the cytoprotective and antioxidant actions of AGE against the cardiotoxic effect of ADR in rats. Six equal groups, control, ADR-treated (single dose of 10 mg/kg on day 8); AGE-treated (one dose of 250 mg/kg for 14 days); AGE plus ADR-treated (one dose of 250 mg/kg AGE for one week plus ADR injection of 10 mg/kg on day 8); ADR plus AGE-treated (single ADR injection of 10 mg/kg on day 8 plus AGE of 250 mg/kg once from 8th to 14th day); combined AGE plus ADR plus AGE-treated (one dose of 250 mg/kg AGE for 14 days plus single ADR injection of 10 mg/kg on day 8). Sera and cardiac samples were collected on day 15 and prepared for histological, ultrastructural and biochemical study. Disorganization, focal degeneration and necrosis with apoptotic changes of the cardiac myofibrils were observed in ADR-treated rats. Also, reduction in level of total creatine kinase, lactic dehydrogenase, alkaline phosphatase enzymes, glutathione, glutathione- peroxidase, superoxide dismutase, and catalase activities and elevation in malondialdehyde concentration were detected in ADR-treated rats. However, combination of AGE attenuated most of the histopathological, ultrastructural, and biochemical changes induced by ADR. Combination of AGE attenuated the cardiotoxic effects-induced by ADR through its antioxidant and cytoprotective potentials. Therefore, AGE can use as adjunct during administration of ADR in cancer therapy.

Chemoprotective role of an extract of the heart of the Phoenix dactylifera tree on adriamycin-induced cardiotoxicity and nephrotoxicity by regulating apoptosis, oxidative stress and PD-1 suppression

Cardiotoxicity and nephrotoxicity due to the abnormal production of free radicals have been observed in patients treated with the anticancer antibiotic adriamycin (ADR). The aim of the present study was to evaluate the role of the heart of palm extract in preventing oxidative stress, cardiotoxicity and nephrotoxicity induced by ADR. In this work, an aqueous ethanolic extract of the heart of the Phoenix dactylifera tree (HP) was investigated. The polyphenol content was evaluated by gas chromatography–mass spectrometry (GC–MS) and High-performance liquid chromatography (HPLC). The protective effect of the HP-extract (250 and 500 mg/kg, p.o.) was evaluated along with ADR administration (cumulative dose 15 mg/kg, IP) in rats. The HP-extract (500 mg/kg) treated group showed significant reductions in cardiotoxicity and nephrotoxicity serum markers, apoptotic percentage, and caspase-3 and cyclooxygenase-2 level, with an improvement in antioxidant enzymes in both heart and kidney homogenate, compared with the ADR-induction group. The cardiac and kidney programmed cell death protein-1 (PD-1) was increased in high dose HP-extract treated rats after being inhibited by ADR administration. In conclusion, the HP-extract might be a promising food supplement for preventing the cardiotoxicity and nephrotoxicity induced by ADR administration.

Ameliorative effect of rosiglitazone, a peroxisome proliferator gamma agonist on adriamycin-induced cardio toxicity via suppressing oxidative stress and apoptosis.

We investigated the rosiglitazone (RSG) effect on adriamycin (ADM)-induced cardio toxicity in experimental animals. Forty adult Wistar male rats were separated into four groups as follows: normal control; RSG (10 mg/kg)-treated; ADM (10 mg/kg)-administered; and ADM (10 mg/kg) + RSG (10 mg/kg)-treated. Serum lipid level, different biochemical biomarkers, histological analysis, and nuclear factor erythroid 2-related factor/heme oxygenase-1 (Nrf2/HO-1), Caspase 3, B-cell lymphoma 2 (Bcl-2), and Bax gene expression were assessed in serum and cardiac tissue samples. Our results show that RSG treatment in ADM-administered animals significantly diminished low-density lipoprotein cholesterol, triglyceride, and total cholesterol, and increases high-density lipoprotein cholesterol (HDL-c) in comparison with the ADM group. RSG treatment reduced the effect of ADM administration on cardiac dysfunction markers such as cardiac troponin T Creatine Kinase-MB, aspartate aminotransferase, and lactate dehydrogenase, showing the amelioration of cardio toxicity in ADM-administered rats. Additionally, RSG treatment significantly decreased the level of malondialdehyde and nitric oxide in cardiovascular tissue. RSG-treated rats in combination with ADM likewise showed a significant increase in reduced glutathione, superoxide dismutase, catalase content, and the activity of glutathione peroxidase (GPx) as compared with ADM group. Moreover, RSG treatment in ADM rats significantly increased an Nrf2 and HO-1 expression in comparison with ADM group. While in apoptosis parameters, RSG treatment in ADM rats significantly diminished a cleaved caspase-3 and Bax expression as well as expanded Bcl-2 expression when contrasted with ADM group of rats. In conclusion, RSG is capable of protecting heart toxicity in ADM-treated animals through defensive effects on oxidative stress and biochemical markers.

Paeonol Reverses Adriamycin Induced Cardiac Pathological Remodeling through Notch1 Signaling Reactivation in H9c2 Cells and Adult Zebrafish Heart.

Adriamycin is a commonly prescribed chemotherapeutic drug for a wide range of cancers. Adriamycin causes cardiotoxicity as an adverse effect that limits its clinical application in cancer treatment. Several mechanisms have been proposed to explain the toxicity it causes in heart cells. Disruption of inherent cardiac repair mechanism is the least understood mechanism of Adriamycin-induced cardiotoxicity. Adriamycin induces pathological remodeling in cardiac cells by promoting apoptosis, hypertrophy, and fibrosis. We found that Adriamycin inhibited Notch1 in a time- and dose-dependent manner in H9c2 cells. We used Paeonol, a Notch1 activator, and analyzed the markers of apoptosis, hypertrophy, and fibrosis in H9c2 cells in vitro and in adult zebrafish heart in vivo as model systems to study Adriamycin-induced cardiotoxicity. Paeonol activated Notch1 signaling and expression of its downstream target genes effectively in the Adriamycin-treated condition in vitro and in vivo. Also we detected that Notch activation using Paeonol protected the cells from apoptosis, collagen deposition, and hypertrophy response using functional assays. We conclude that Adriamycin induced cardiotoxicity by promoting the pathological cardiac remodeling through inhibition of Notch1 signaling and that the Notch1 reactivation by Paeonol protected the cells and reversed the cardiotoxicity.

Potential Protective Effect of Achillea fragrantissima against Adriamycin-Induced Cardiotoxicity in Rats via an Antioxidant and Anti-Inflammatory Pathway.

Adriamycin (Adr) is a cytotoxic anthracycline agent that is utilized to manage many types of tumors, but its clinical use is undesirable due to severe cardiotoxicity. The present study aimed to investigate the cardioprotective effect of Achillea fragrantissima (A. fragrantissima) against Adr-induced cardiotoxicity through the antioxidant and anti-inflammatory metabolic pathways. A single dose of Adr was injected in rats to induce cardiotoxicity. Rats are divided into 5 groups, control, A. fragrantissima 800, Adr, A. fragrantissima 400 + Adr, and A. fragrantissima 800 + Adr. 72 h after Adr administration, electrocardiographic (ECG) study was performed for all rats. Serum and hearts were then collected for biochemical and histopathological studies. A. fragrantissima ameliorated Adr-induced ST-segment elevation. It reduced Adr-induced elevation in lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), thiobarbituric acid reactive substance (TBARS), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6. It also protected against Adr-induced histopathological changes. Pretreatment with the extract increased heart tissue contents of glutathione peroxidase (GSH-PX) and reduced glutathione (GSH). Phytochemical analysis of the extract revealed that it is rich in phenolic and flavonoid active constituents. The results of this study revealed that A. fragrantissima extract ameliorates Adr-induced cardiotoxicity via an antioxidant and anti-inflammatory mechanisms. Further studies are warranted in order to recognize the precise active constituents of this natural extract which are responsible for the antioxidant and anti-inflammatory actions.

Chemosensitization and mitigation of Adriamycin-induced cardiotoxicity using combinational polymeric micelles for co-delivery of quercetin/resveratrol and resveratrol/curcumin in ovarian cancer

This work looks to improve the efficacy of Adriamycin (ADR) while mitigating its cardiotoxicity using combinations of micellar resveratrol (R): quercetin (Q) (mRQ) or R: curcumin (C) (mRC) in healthy mice and ovarian cancer xenograft models. Ovarian cancer cells, ES2-Luc, or A2780ADR are inoculated in mice (n =4/group) and sorted into eight cohorts. Mice are treated weekly for 4 weeks with ADR, ADR+mRQ, ADR+mRC, or controls (saline, empty micelles, ADR+EM, mRQ, or mRC). To evaluate the degree of cardioprotection, serum is collected to determine the cardiac Troponin I (cTnI). Cardiac tissue is collected for morphological evaluation and evaluation of creatine kinase levels. Our results indicate that mRQ+ADR is statistically significant in tumor reduction in xenograft models. In healthy mice, the left ventricular ejection fraction and fractional shortening in the ADR treated group is most compromised. Co-administration of mRQ with ADR can reduce ADR dosing through chemosensitization while being cardioprotective.

Protective effect of edaravone on adriamycin-induced cardiotoxicity in rats

Amac : Adriamisin (ADR), kemoterapide yaygin olarak kullanilan antineoplastik bir ilactir, ancak kardiyotoksisitesi, bu ilacin klinik kullanimini sinirlayan en onemli yan etkidir. Bu calismada, ratlarda adriamisin ile olusturulan kardiyotoksisite modelinde guclu bir antioksidan olan edaravonun (EDO) etkisini elektrokardiyografik (EKG), biyokimyasal ve sintigrafik yontemlerle arastirdik. Yontem: Yirmi sekiz eriskin erkek Wistar-Albino rat rastgele dort gruba ayrildi; kontrol (CON); Adriamisin (ADR); edaravon (EDO), edaravon + adriamisin (EDO + ADR). Ratlarda kardiyotoksisite, 5., 6. ve 7. gunlerde 24 saatlik (h) araliklarla ADR enjeksiyonu (kumulatif doz: 18 mg / kg, intraperitoneal-i.p.-) ile induklenmistir. EDO + ADR grubu uygulamasinda ratlara 7 gun boyunca EDO (30 mg / kg / gun, i.p.) uyguladi ve 5., 6. ve 7. gunlerde ADR (18 mg / kg, i.p.) enjekte edildi. 8. gunde elektrokardiyografi (EKG), biyokimyasal ve teknesyum-99m pirofosfat ( 99m Tc-PYP) sintigrafik parametreleri degerlendirildi. Bulgular: ADR induksiyonu EKG paterninde degisikliklere neden oldu; kalp atisi, P dalgasi ve QRS kompleks suresi azaldi, hem ST-segment genligini hem de QT suresini arttirdi (p < 0,001), ayrica biyokimyasal belirteclerde artis izlendi [kan ure azotu (BUN), kreatin kinaz (CK), kardiyak troponin T (cTnT)] ve yuksek 99mTc-PYP uptakei seviyesi (p < 0,001). EDO tedavisi, ratlarda ADR’nin neden oldugu kardiyotoksisite parametrelerinin tumunu engelledi, EKG’deki tum ADR’e bagli anormallikler, 99m Tc-PYP uptakei ve serum BUN, CK ve cTnT seviyeleri onemli olcude azaldi ( p <0.001). Sonuc: Verilerimiz, EDO’nun ADR kaynakli kardiyotoksisite uzerinde kardiyoprotektif etkilere sahip oldugunu gostermektedir. Ayni zamanda, bu calisma 99m Tc-PYP’nin ADR’nin neden oldugu kardiyotoksisitenin erken teshisi icin non-invaziv bir yontem olarak kullanabilecegini dusundurmektedir.

Glibenclamide exacerbates adriamycin-induced cardiotoxicity by activating oxidative stress-induced endoplasmic reticulum stress in rats.

Adriamycin (ADR) is a chemotherapeutic drug used to treat tumors in a clinical setting. However, its use is limited by a side effect of cardiotoxicity. Glibenclamide (Gli), an inhibitor of mitochondrial ATP-dependent potassium (K-ATP) channels, blocks the cardioprotective effects of mitochondrial K-ATP channel openers and induces apoptosis in rodent pancreatic islet β-cell lines. However, little is known about the role of Gli in ADR-induced cardiotoxicity. The present study was designed to investigate the impact of Gli on ADR-induced cardiotoxicity in rats. A total of 60 male Sprague-Dawley rats were divided into the following 4 groups: i) Control; ii) Gli; iii) ADR; and iv) Gli+ADR (n=15 in each). The rats in the ADR and Gli+ADR groups were treated with ADR (intraperitoneal, 2.5 mg/kg/week) for 6 weeks. The rats in the Gli and Gli+ADR groups received Gli at a dose of 12 mg/kg/day via gastric lavage for 30 days from the eighth week of the study. Following the completion of Gli treatment, cardiac function was assessed by echocardiography, and the rats were sacrificed. The hearts were subsequently harvested for analysis. The rats in the ADR group demonstrated significantly impaired cardiac function and increased levels of oxidative stress, endoplasmic reticulum stress (ERS) and apoptosis in the heart compared with rats in the control and Gli groups (without ADR treatment). These abnormalities were exacerbated by Gli in the Gli+ADR group. Gli treatment decreased cardiac function and significantly increased oxidative stress, ERS and apoptosis levels in myocardial tissues in rats treated with ADR. The findings indicated that Gli triggers oxidative stress-induced ERS, and thus exacerbates ADR-induced cardiotoxicity in rats.

GW28-e0558 Inhibition of TRPA1 prevents Adriamycin-induced acute cardiotoxicity through suppression of oxidative stress and inflammation responses

To investigate the potential role of TRPA1 in the development of doxorubicin-induced acute cardiotoxicity 80 experimental male C57BL/6J mice were randomly divided into four groups: sham + vehicle (n=20), sham + HC-030031(HC) (n=20), ADR + vehicle (n=20), and ADR + HC-030031(HC) (n=20). HC-030031 (

Prevention of Adriamycin induced cardiotoxicity in rats — A comparative study with subacute angiotensin-converting enzyme inhibitor and nonselective beta blocker therapy

Back groundCardiotoxicity confines the usage of Adriamycin in clinical practice as it can develop cardiac impediments up to 10years after the termination of therapy. Even though, no specific therapeutic strategies are available for treating adriamycin-induced cardiotoxicity, beta-adrenergic blockers (βB) and angiotensin-converting enzyme (ACE) inhibitors are known to prevent its progression into failure. In this scenario, we attempted to compare the pharmacological outcome of sub-acute βB and ACE inhibitor treatments in preventing adriamycin-induced cardiotoxicity by analysing the differences between them. MethodsRats received a single bolus dose of adriamycin (10mg/kg) on day one and treated with either Carvedilol (10mg/kg) (CAR) or Captopril (50mg/kg) (CAP) once daily for 28days. Cardiac morphology, systolic and diastolic functions were evaluated by 2D trans-thoracic echocardiography. Cardiac Troponin and Ck MB levels were measured to analyse the myocyte damage. Myocardial lipid peroxidation, IL1β levels and caspase 3 activity were evaluated as the markers of oxidative stress, inflammation and apoptosis respectively. ResultsBoth treatments had reduced the adriamycin induced cardiotoxicity. Whereas CAP treatment showed a better reduction of inflammation, superior preservation of posterior wall architecture and enhanced improvement in relative wall thickness when compared to CAR. Oxidative stress, caspase 3 activity and markers of myocyte damage were better recovered with CAR treatment while other parameters were found to be identically attenuated. ConclusionThe present study found an identical therapeutic outcome from ACE inhibition and β blockade with a better attenuation of inflammation and structural preservation with ACE inhibition and superior antioxidant and antiapoptotic effect with βB treatment.

1576P - Enzymatic action of NQO1 attenuates adriamycin-induced cardiotoxicity in mice

1576P - Enzymatic action of NQO1 attenuates adriamycin-induced cardiotoxicity in mice

GW26-e2914 A study of the mechanism of valsartan pre-protecting adriamycin-induced cardiotoxicity

GW26-e2914 A study of the mechanism of valsartan pre-protecting adriamycin-induced cardiotoxicity

Ginsenoside Rg3 antagonizes adriamycin-induced cardiotoxicity by improving endothelial dysfunction from oxidative stress via upregulating the Nrf2-ARE pathway through the activation of akt

BackgroundAdriamycin (ADM) is an antineoplastic agent that is effective against a wide range of cancers, but cardiac toxicity limits its clinical application. Ginsenoside Rg3 (Rg3), an anti-cancer active ingredient of Panax ginseng, was reported to have anti-oxidative, anti-apoptotic, and cardioprotective properties. PurposeThe current study aimed to investigate the possible protective effect of Rg3 against ADM-induced cardiotoxicity. Study designThe activity of Rg3 to improve endothelial dysfunction was processed both in vivo and in vitro. MethodsWe investigated the cardioprotective effect of Rg3 on ADM treated rats by echocardiography. The endothelial dysfunction was assessed using an aortic ring assay. Cardiac microvascular endothelial cells were cultured to investigate the effects of Rg3 on ADM-treated cells. ResultsResults showed that Rg3 could ameliorate the decrease in the ejection fraction and fractional shortening that was induced by ADM, and improve the left ventricular outflow. The aortic ring assay showed that Rg3 could partially recover the abnormal vascular function. In vitro studies showed that Rg3 could promote cell viability to attenuate ADM induced oxidative damage and apoptosis. This counteraction was achieved partially via activation of the Nrf2-ARE pathway through the activation of Akt. ConclusionThese findings elucidated the potential of Rg3 as a promising reagent for treating ADM-induced cardiotoxicity in clinic.