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Representative image of rat heart ultrasound (US). Cardiac function evaluated by echocardiography. M-Mode imaging with the measurements of diastolic left ventricular internal dimensions (LVIDd), systolic left ventricular internal dimensions (LVIDs), interventricular septal end diastole (IVSd), and systole (IVSs) and left ventricular posterior wall end diastole and (LVPWd) and systole (LVPWs), left ventricular ejection fraction (EF) calculated after the Teicholz method, shortening fraction (FS) in control (A) vs DOX-treated (B) rats at 10 days
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Drug-induced cardiotoxicity is a life-threatening side effect of doxorubicin (DOX) treatment that impacts patient prognosis and survival. In the majority of cases, the acute clinical form often remains asymptomatic, with few patients presenting rather nonspecific electrocardiographic abnormalities. While chronic toxicity has been more widely studie...
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... Doxorubicin (DOX), represented in Figure 1, is an anthracycline used as a chemotherapeutical drug to treat several cancer types, including breast cancer [5]. However, the clinical use of DOX requires attention to its side effects, particularly its dose-dependent cardiotoxicity [6]. In order to avoid these side effects, new formulations with reduced toxicity and increased efficacy to improve patient treatment and breast cancer [5]. ...
... In order to avoid these side effects, new formulations with reduced toxicity and increased efficacy to improve patient treatment and breast cancer [5]. However, the clinical use of DOX requires attention to its side effects, particularly its dose-dependent cardiotoxicity [6]. In order to avoid these side effects, new formulations with reduced toxicity and increased efficacy to improve patient treatment and comfort are necessary. ...
Drug delivery selectivity is a challenge for cancer treatment. A hybrid pegylated pH-sensitive liposome–extracellular vesicle isolated from human breast cancer cell MDA-MB-231 was developed to investigate its in vitro activity against breast cancer cells of different molecular profiles to overcome this inconvenience. The hybrid nanosystem was produced by film hydration, and doxorubicin (DOX) was encapsulated in this system using the ammonium sulfate gradient method. The characterization of this hybrid nanosystem revealed a mean diameter of 140.20 ± 2.70 nm, a polydispersity index of 0.102 ± 0.033, an encapsulation efficiency of doxorubicin of 88.9% ± 2.4, and a great storage stability for 90 days at 4 °C. The fusion of extracellular vesicles with liposomes was confirmed by nanoflow cytometry using PE-conjugated human anti-CD63. This hybrid nanosystem demonstrated cytotoxicity against human breast cancer cell lines with different molecular subtypes, enhanced anti-migration properties, and exhibited similar cellular uptake to the free DOX treatment. Preliminary acute toxicity assessments using Balb/C female mice indicated a median lethal dose of 15–17.5 mg/kg, with no evidence of splenic, liver, heart, bone marrow, and renal damage at a dose of 15 mg/kg. These findings suggest the hybrid formulation as a versatile nanocarrier for the treatment of various breast cancer subtypes.
... To evaluate cardiotoxicity, we assessed cardiac function by echocardiogram, which showed impairment of diastolic and systolic function in rats that received doxorubicin, as previously shown in other studies [50][51][52][53][54][55][56]. Interestingly, we also observed higher IVRT in DL than D, which may suggest an impairment in diastolic function when both drugs are administered together. ...
Doxorubicin is an effective drug for cancer treatment; however, cardiotoxicity limits its use. Cardiotoxicity pathophysiology is multifactorial. GLP-1 analogues have been shown to reduce oxidative stress and inflammation. In this study, we evaluated the effect of pretreatment with liraglutide on doxorubicin-induced acute cardiotoxicity. A total of 60 male Wistar rats were allocated into four groups: Control (C), Doxorubicin (D), Liraglutide (L), and Doxorubicin + Liraglutide (DL). L and DL received subcutaneous injection of liraglutide 0.6 mg/kg daily, while C and D received saline for 2 weeks. Afterwards, D and DL received a single intraperitoneal injection of doxorubicin 20 mg/kg; C and L received an injection of saline. Forty-eight hours after doxorubicin administration, the rats were subjected to echocardiogram, isolated heart functional study, and euthanasia. Liraglutide-treated rats ingested significantly less food and gained less body weight than animals that did not receive the drug. Rats lost weight after doxorubicin injection. At echocardiogram and isolated heart study, doxorubicin-treated rats had systolic and diastolic function impairment. Myocardial catalase activity was statistically higher in doxorubicin-treated rats. Myocardial protein expression of tumor necrosis factor alpha (TNF-α), phosphorylated nuclear factor-κB (p-NFκB), troponin T, and B-cell lymphoma 2 (Bcl-2) was significantly lower, and the total NFκB/p-NFκB ratio and TLR-4 higher in doxorubicin-treated rats. Myocardial expression of OPA-1, MFN-2, DRP-1, and topoisomerase 2β did not differ between groups (p > 0.05). In conclusion, doxorubicin-induced cardiotoxicity is accompanied by decreased Bcl-2 and phosphorylated NFκB and increased catalase activity and TLR-4 expression. Liraglutide failed to improve acute doxorubicin-induced cardiotoxicity in rats.
... 11,12 Cardiotoxicity in particular is one of the main concerns with the delivery of DOX that restricts its clinical application. 13,14 Due to these dose-limiting side effects that prevent DOX from reaching its full antitumor potential, new delivery mechanisms are being investigated to more adequately and specifically deliver DOX to its intended target. One of the most promising methods to do so is to encapsulate DOX within nanocarriers such as polymer nanoparticles (NPs) or liposomes, as demonstrated with the FDA-approved therapeutic Doxil. ...
Doxorubicin (DOX) is a chemotherapy agent commonly used to treat triple-negative breast cancer (TNBC), but it has insufficient efficacy against the disease and considerable toxicity due to its off-target delivery. To improve the specificity of DOX for TNBC, we encapsulated it in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) coated with antibodies against Frizzled7 (FZD7), a receptor that is overexpressed on TNBC cells and which is a key activator of the Wnt signaling pathway. In vitro studies show that DOX encapsulation does not hinder its ability to localize to the nucleus in human TNBC cell cultures and that DOX delivered via NPs induces apoptosis and DNA damage via H2A.X phosphorylation to the same degree as freely delivered DOX. FZD7-targeted NPs delivering DOX caused significantly greater inhibition of metabolic activity and led to a smaller cell population following treatment when compared to freely delivered DOX or DOX-loaded NPs coated only with poly(ethylene glycol) (PEG). The FZD7 antibodies additionally provided significant levels of Wnt pathway inhibition, as demonstrated by an increase in β-catenin phosphorylation, indicative of β-catenin destruction and downregulation. These results show that FZD7-targeted platforms have great promise for improving the therapeutic window of otherwise toxic chemotherapies like DOX in TNBC and other cancers that display the overexpression of FZD7 receptors.
... It is also important to note that, despite a considerably lower dose for DOX in combination therapy, its impact on the cell viability did not differ for the MDA-MB-231 cells, which can be attributed to the combination therapy. This is especially significant considering the DOX-related cardiotoxicity, which drastically reduces the efficiency and effectiveness of the therapy [23]. Therefore, it is noteworthy that achieving a lower dose of DOX through addition of ABE to the therapy planning can be of significant importance for patients who can not stay on the high-dose treatment plan. ...
Due to lack of clinical biomarkers, Triple Negative Breast Cancer (TNBC) is more likely to have spread to other tissues at time of diagnosis and therapy planning generally involves use of cytotoxic chemotherapy agents, such as Doxorubicin. We aimed to investigate possible advantages of using combination strategy using Doxorubicin alongside Abemaciclib. After determining the IC50 values for Doxorubicin (DOX) and Abemaciclib (ABE); CompuSyn and ComBenefit software were used to reveal the effect resulting from the combination of two drugs. Following the determined effect, cell death was revealed by fluorescence microscopy and a colony forming assay was performed to see the potential of even a single cancer cell with adhesive character to survive over time and form a clone of itself. Detection of changing antioxidant activity following DOX, ABE and DOX+ABE combination therapy in MDAMB231 cells was determined by measuring MDA, SOD and GSH activities. The expression of Cleaved Caspase 3, PARP, Cleaved PARP, Cdk2 and Bax, which changed as a result of DOX, ABE and DOX+ABE application, was shown by Western Blotting.Cyclin-dependent kinase inhibitors appear as promising agents in therapy planning for breast cancer due to their prominent role in cell cycle regulation, where the number of studies interrogating its efficiency in the treatment of cancer such as TNBC is limited. For this reason, in this study, we aimed to determine the impact of the combined use of the CDK4/6 inhibitors ABE and DOX on the cytotoxicity, apoptotic homeostasis, alterations in antioxidative mechanisms, and the molecular pathways that they utilize. Our results showed that when used in combination, Doxorubicin and Abemaciclib showed a synergistic effect on TNBC cell line MDA-MB-231.
... Apoptosis caused by DOX is mediated by both internal and external signalling mechanisms (Sangweni et al. 2022). The present study showed that the perturbances in redox balance, in ammatory, and apoptotic processes caused by a single dose of DOX were major in accordance with Dulf et al. 2023. The antianginal drug Trimetazidine (TMZ) protects cardiomyocytes against ischemia-induced damage in patients with stable coronary artery disease. ...
Chemotherapeutic medications are commonly used for treating a variety of cancer types; nevertheless, they can also have biological adverse effects, particularly on non-tumor cells, and regularly upset the physiological balance in a number of different organs, specifically the heart. The current inquiry's objective was to determine how well Cannabidiol (CBD) oil mitigated the cardiotoxicity caused by Doxorubicin (DOX). Five equal groups of fifty male Sprague-Dawley rats with 150±25g were molded. Group I received distilled water orally, while Group II received an intraperitoneal dose of DOX (18 mg/kg bwt). CBD was given to Group III, while 1 ml CBD (26 mg/kg bwt) was given to Group IV, and Trimetazidine (10 mg/kg bwt) was given to Group V. Both groups (IV and V) also got a single dose of Doxorubicin (18 mg/kg bwt) on the 11th day. Heart histology, biochemical measurements, immunological tests, and gene expression were examined. In addition to bringing ECG and blood pressure back to normal, the administration of CBD (26 mg/kg bwt) showed a substantial improvement in cardiac enzyme activity (Troponin I and CK-MB), and is related to decreasing cholesterol and triglycerides. Additionally, there was a reduction in oxidative stress, as measured by MDA, and inflammatory markers (IL6 and TNF-a) and improvement in SOD, GSH in cardiac homogenate. There has also been a noticeable drop in the expression of the frequency concentration of IL6R associated with improved heart tissue. CBD may be protective because of its anti-inflammatory and antioxidant assets.
... Autophagy functions as a major cytoprotective process by preserving cellular homeostasis and recy-cling cytoplasmic constituents. However, studies suggest that autophagy is a primary form of cell death and implicates autophagic cell death in the pathological process of DOX-induced cardiomyocyte death [28]. Anthracyclines have been found to induce dysregulated autophagy, which leads to an excessive amount of cardiomyocyte death [29]. ...
... Current studies on the effect of anthracyclines on autophagy have reported conflicting results. Some studies have reported that anthracyclines induce autophagy [28], while others have reported that anthracyclines inhibit autophagy [32,33]. Similarly, studies on the effects of genetic or pharmacological suppression of autophagy have yielded mixed results, with some indicating protective effects [34,35], while others demonstrate that sustained reduction of autophagy cannot maintain protection against DOXIC [36,37]. ...
... Previous studies indicated that doxorubicin-induced cardiotoxicity involved in autophagy, apoptosis, oxidative stress, inflammation, mitochondrial damage, calcium homeostasis disturbance, ferroptosis and other biological processes [29]. Among them, autophagyapoptosis is the core mechanism of doxorubicin-induced myocardial damage [30]. It was found that doxorubicin over-activated the autophagy in cardiomyocytes, caused autophagic cell death, and mediated myocardial remodeling. ...
Context: Autophagy-apoptosis is the core mechanism of doxorubicin-induced myocardial injury. miR-30a is a pivotal factor in the regulation of autophagy and apoptosis. It remains unclear whether SMI exerts cardioprotective effect by regulating autophagy and apoptosis via miR-30a.
Objective: This study evaluates the effects of SMI on ameliorating doxorubicin-induced myocardial injury.
Materials and Methods: The level of LDH and CK, and the expression of miR-30a was detected. mCherry-EGFP-LC3B double fluorescence was used to observe autophagy flow. Apoptosis was detected by Annexin V/PI staining. Western Blot was used to estimate the expression of autophagy related proteins and apoptosis-related proteins.
Results: Compared with the control group, there were evidently decreased cell viability, elevated level of LDH and CK, down-regulated expression of miR-30a in the model group. Data from Western blot and fluorescence indicated that doxorubicin contributed to the elevated autophagy and apoptosis. Compared with the model group, there were increased cell viability, decreased level of LDH and CK, and up-regulated expression of miR-30a in the Shenmai group and the Shenmai + miR-30a inhibitor group. Meanwhile, the results manifested that there were suppressed autophagy flow accompanied by the down-regulated expression of Beclin-1, LC3-II, LC3-II/LC3-I and up-regulated expression of p62 protein, and declined apoptosis rate accompanied by the up-regulated Bcl2 expression and the down-regulated expression of Bax, Cleaved Caspase-9, Cleaved Caspase-9/Caspase-9, Cleaved Caspase-3, Cleaved Caspase-3/Caspase-3 in the Shenmai group and the Shenmai + miR-30a inhibitor group.
Discussion and Conclusion: Shenmai injection inhibited autophagy and apoptosis via miR-30a, thereby alleviating doxorubicin-induced myocardial injury.
... In addition, the alterations in 4HNE-adducted protein in EVs occurred before serum changes in NT-proBNP, the traditional cardiac marker. These results are consistent with a previous report in which oxidative homeostasis was found to be disturbed as early as 7 days after DOX treatment and that these changes happened before the significant rise in NT-proBNP (Dulf et al., 2023). ...
Late-onset cardiomyopathy is becoming more common among cancer survivors, particularly those who received doxorubicin (DOXO) treatment. However, few clinically available cardiac biomarkers can predict an unfavorable cardiac outcome before cell death. Extracellular vesicles (EVs) are emerging as biomarkers for cardiovascular diseases and others. This study aimed to measure dynamic 4-hydroxynonenal (4HNE)-adducted protein levels in rats treated chronically with DOXO and examine their link with oxidative stress, antioxidant gene expression in cardiac tissues, and cardiac function. Twenty-two male Wistar rats were randomly assigned to receive intraperitoneal injection of normal saline (n = 8) or DOXO (3 mg/kg, 6 doses, n = 14). Before and after therapy, serum EVs and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were determined. Tunable resistive pulse sensing was used to measure EV size and concentration. ELISA was used to assess 4HNE-adducted protein in EVs and cardiac tissues. Differential-display reverse transcription-PCR was used to quantitate cardiac Cat and Gpx1 gene expression. Potential correlations between 4HNE-adducted protein levels in EVs, cardiac oxidative stress, antioxidant gene expression, and cardiac function were determined. DOXO-treated rats showed more serum EV 4HNE-adducted protein than NSS-treated rats at day 9 and later endpoints, whereas NT-proBNP levels were not different between groups. Moreover, on day 9, surviving rats' EVs had higher levels of 4HNE-adducted protein, and these correlated positively with concentrations of heart tissue 4HNE adduction and copy numbers of Cat and Gpx1, while at endpoint correlated negatively with cardiac functions. Therefore, 4HNE-adducted protein in serum EVs could be an early, minimally invasive biomarker of the oxidative response and cardiac function in DOXO-induced cardiomyopathy.
The effects of N'-(2,6-dimethoxybenzylidene)-3-(4-methoxyphenyl) acrylohydrazide (KAD 9) on iron-induced cardiac injury was investigated. Evaluations of the iron chelating capability, ferric-reducing antioxidant power (FRAP), as well as DPPH free radical scavenging activity of KAD 9 were performed. The oxidative cardiac injury induced by 0.1 mM FeSO4 was treated with varied doses of KAD 9 ex vivo. Comparing KAD 9 to conventional quercetin, the DPPH radical scavenging ability of KAD 9 significantly rises with concentration (p<0.05). The cardiac injury was generated, and this resulted in decreased malondialdehyde (MDA), catalase (CAT), ATPase, and ENTPDase activity (p<0.05). A notable increase in GSH level was seen in KAD 9 treated group. Furthermore, it was observed that KAD 9 had closer binding affinity with ATPase and ENTPDase. Due to its ability to regulate nucleotide hydrolysis and lessen oxidative stress, KAD 9 has the potential to both treat and protect against oxidative cardiac injury.
Introduction: Dilated cardiomyopathy (DCM) is a fatal myocardial condition with ventricular structural changes and functional deficits, leading to systolic dysfunction and heart failure (HF). DCM is a frequent complication in oncologic patients receiving Doxorubicin (Dox). Dox is a highly cardiotoxic drug, whereas its damaging spectrum affects most of the organs by multiple pathogenic cascades. Experimentally reproduced DCM/HF through Dox administrations has shed light on the pathogenic drivers of cardiotoxicity. Growth hormone (GH) releasing peptide 6 (GHRP-6) is a GH secretagogue with expanding and promising cardioprotective pharmacological properties. Here we examined whether GHRP-6 administration concomitant to Dox prevented the onset of DCM/HF and multiple organs damages in otherwise healthy rats.
Methods: Myocardial changes were sequentially evaluated by transthoracic echocardiography. Autopsy was conducted at the end of the administration period when ventricular dilation was established. Semiquantitative histopathologic study included heart and other internal organs samples. Myocardial tissue fragments were also addressed for electron microscopy study, and characterization of the transcriptional expression ratio between Bcl-2 and Bax. Serum samples were destined for REDOX system balance assessment.
Results and discussion: GHRP-6 administration in parallel to Dox prevented myocardial fibers consumption and ventricular dilation, accounting for an effective preservation of the LV systolic function. GHRP-6 also attenuated extracardiac toxicity preserving epithelial organs integrity, inhibiting interstitial fibrosis, and ultimately reducing morbidity and mortality. Mechanistically, GHRP-6 proved to sustain cellular antioxidant defense, upregulate prosurvival gene Bcl-2, and preserve cardiomyocyte mitochondrial integrity. These evidences contribute to pave potential avenues for the clinical use of GHRP-6 in Dox-treated subjects.
