Doxorubicin-induced Cardiac Toxicity Research Articles

Cardioprotective effect of chelidonic acid against doxorubicin-induced cardiac toxicity in rats

Introduction and objectivesThe current study evaluates the effect of chelidonic acid on doxorubicin-induced cardiac toxicity. Chelidonic acid (CA) is a natural pyran-skeleton heterocyclic compound found in rhizomes of the perennial plant, celandine (Chelidonium majus). MethodsWistar rats were given an intraperitoneal injection of doxorubicin (1.25 mg/kg, cumulative dose of 20 mg/kg) four times per week for a duration of four weeks to induce cardiotoxicity. CA treatment (10, 20, and 40 mg/kg orally for four weeks) was started together with doxorubicin. ResultsCA treatment reduced myocardial damage and improved cardiac dysfunction in doxorubicin-treated rats. It improved blood pressure, restored ST wave height and normalized the QTc interval compared to the rats treated only with doxorubicin. Administration of CA for four weeks reduced left ventricular end-diastolic pressure. Moreover, CA treatment decreased the level of cardiac markers such as creatine kinase-myocardial band (CK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and cardiac troponin-T. Masson's trichrome, hematoxylin, and eosin staining of heart tissue revealed that CA attenuated the deleterious effects of doxorubicin and prevented further damage and fibrosis in rats. ConclusionThe study findings confirm that CA treatment can protect the myocardium against doxorubicin-induced cardiotoxicity.

Beneficial effects of Bacopa monnieri (brahmi) in Doxorubicin-induced cardiotoxicity in rats

Cancer, a leading global cause of death, drives research for safer treatments. Doxorubicin is an effective anticancer drug but is associated with cardiotoxicity as a characteristic adverse effect. Bacopa monnieri, a traditional Ayurvedic herb rich in antioxidants, emerges as a potential adjunct in cancer treatment. The study aims to explore Bacopa monnieri's impact on doxorubicin-induced cardiotoxicity. The study was conducted in 30 rats with 6 rats in each of the 5 groups: Group 1 was administered distilled water; Group 2 received Doxorubicin at 5 mg/kg by IP on days 7, 14, and 21. Groups 3, 4 and 5 were administered Bacopa monnieri at 75mg/kg, 150mg/kg, and 250mg/kg orally daily doses along with Doxorubicin at 5mg/kg by IP on days 7,14 and 21. The Bacopa monnieri-treated groups compared to the Doxorubicin(Dox) group showed a significant reduction in aspartate aminotransferase (AST), troponin I, and malondialdehyde (MDA) levels while the levels of antioxidants Superoxide dismutase (SOD), and Glutathione (GSH) increased. Histopathology showed fibrosis and inflammation in the Doxorubicin group while restoration of normal cardiac tissue in the Bacopa monnieri-treated group. The study illustrates Bacopa monnieri's ability to alleviate Doxorubicin-induced cardiac toxicity by its antioxidant properties.

Zamzam Water Mitigates Cardiac Toxicity Risk through Modulation of GUT Microbiota and the Renin-angiotensin System.

Cardiovascular diseases (CVDs) continue to exert a substantial global influence in specific areas due to population growth, aging, microbiota, and genetic/environmental factors. Drinking water has a strong impact on the health of an individual. Further, emerging evidence has highlighted the therapeutic potential and benefits of Zamzam water (Zam). We investigated the influence of Zam on doxorubicin-induced cardiac toxicity, elucidating its consequential effects on GUT microbiota dysbiosis and hepatic and renal functions. Male rats were categorized into four groups: Group 1 as Normal control (NC), Group 2 as Zamzam control (ZC), Group 3 Disease control (DC) and Group 4 as Therapeutic control (DZ) treated with Zam against doxorubicin-induced disease at a dose of 1mg/kg boy weight) intraperitoneally (i.p). Significant dysbiosis in the composition of GM was observed in the DC group along with a significant decrease (p < 0.05) in serum levels of Zinc, interleukin-10 (IL-10), IL-6 and Angiotensin II (Ang II), while C-reactive protein (CRP), fibrinogen, and CKMB increased significantly (restoration of Zinc ions (0.72 ± 0.07 mcg/mL) compared to NC. Treatment with Zamzam exhibited a marked abundance of 18-times to 72% in Romboutsia, a genus of firmicutes, along with lowering of Proteobacteria in DZ followed by significant restoration of Zinc ions (0.72 ± 0.07 mcg/mL), significant (p ˂ 0.05) reduction in CRP (7.22 ± 0.39 mg/dL), CKMB (118.8 ± 1.02 U/L) and Fibrinogen (3.18 ± 0.16 mg/dL), significant (p < 0.05) increase in IL-10 (7.22 ± 0.84 pg/mL) and IL-6 (7.18 ± 0.40 pg/ml), restoration of Ang II (18.62 ± 0.50 nmol/mL/min), marked increase in renin with normal myocyte architecture and tissue orientation of kidney, and restoration of histological architecture of hepatocyte. Zam treatment mitigated cardiac toxicity risk through the modulation of GUT microbiota and the renin-angiotensin system and tissue histology effectively.

Effects of Semaglutide in Doxorubicin-Induced Cardiac Toxicity in Wistar Albino Rats.

Doxorubicin (DOX) is used to treat various types of cancers. However, its use is restricted by cardiotoxicity, a leading cause of morbidity and mortality. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) may be associated with cardioprotective properties. This study aims to determine the protective effects of different semaglutide (SEM) doses on DOX-induced cardiotoxicity in a rat model. Thirty-five female Wistar rats were divided into five groups. The first group received distilled water as a negative control (NC); the positive control (PC) group received distilled water plus DOX; the third group (SL) received a low dose of SEM (0.06 mg/kg) plus DOX; the fourth group (SM) received a moderate dose of SEM (0.12 mg/kg) plus DOX; and the fifth group (SH) received a high dose of SEM (0.24 mg/kg) plus DOX. Blood samples were collected on day 8 to assess serum troponin, lactate dehydrogenase (LDH), creatine phosphokinase (CPK), total lipid profile, and vascular cell adhesion molecule 1 (VCAM-1). Cardiac tissue was sent for histopathological analysis. DOX increased the total cholesterol (TC), low-density lipoprotein (LDL), triglyceride (TG), LDH, and CKP levels. Moderate and high doses of semaglutide significantly reduced serum cholesterol levels (*p = 0.0199), (**p = 0.0077), respectively. A significant reduction (***p = 0.0013) in total body weight after treatment with SEM was observed in the SL group and a highly significant reduction (****p < 0.0001) was observed in the SM and SH groups. SEM at all doses reduced CPK levels. The SL group showed a significant reduction in troponin level (*p=0.0344). Serum LDH levels were reduced by all three SEM doses. The histopathological findings support the biochemical results. Semaglutide may possess cardioprotective properties against DOX-induced cardiotoxicity in a rat model by decreasing serum biochemical markers of cardiotoxicity.

Carnosic acid mitigates doxorubicin-induced cardiac toxicity: Evidence from animal and cell model investigations.

Utilization of doxorubicin (DOX) as a chemotherapy medication is limited due to its cardiotoxic effects. Carnosic acid exerts antioxidant, anti-inflammatory, besides cytoprotective effects. The objective of this study was to investigate the ability of carnosic acid to protect rat hearts and the MCF7 cell line against cardiotoxicity induced by DOX. The study involved the classification of male Wistar rats into seven groups: 1) Control 2) DOX (2 mg/kg, every 48h, IP, 12d), 3-5) Carnosic acid (10, 20, 40 mg/kg/day, IP, 16d)+ DOX, 6) Vitamin E (200 mg/kg, every 48h, IP, 16d)+ DOX 7) Carnosic acid (40 mg/kg/day, IP, 16d). Finally, cardiac histopathological alterations, ECG factors, carotid blood pressure, left ventricular function, heart-to-body weight ratio, oxidative (MDA, GSH), inflammatory (IL-1β, TNF-α), plus apoptosis (caspase 3, 8, 9, Bcl-2, Bax) markers were evaluated. DOX toxicity and carnosic acid ameliorative effect were evaluated on MCF7 cells using the MTT assay. DOX augmented the QRS duration, QA, RRI, STI, and heart-to-body weight ratio, and reduced HR, LVDP, Min dP/dt, Max dP/dt, blood pressure, boosted MDA, TNF-α, IL1-β, caspase 3,8,9, Bax/Bcl-2 ratio, decreased GSH content, caused fibrosis, necrosis, and cytoplasmic vacuolization in cardiac tissue but carnosic acid administration reduced the toxic effects of DOX. The cytotoxic effects of DOX were not affected by carnosic acid at concentrations of 5 and 10 μM. Carnosic acid as an anti-inflammatory and antioxidant substance is effective in reducing DOX-induced damage by enhancing antioxidant defense and modifying inflammatory signal pathway activity and can be used as an adjunct in treating DOX cardiotoxicity.

The Occurrence of Infection and TP53 Mutation Are Risk Factors for Cardiovascular Toxicity of Acute Myeloid Leukemia Induction Therapy

Introduction: For almost 50 years,induction therapy (IT) is the standard of care for acute myeloid leukemia (AML) patients. Nevertheless, little is known about cardiovascular (CV) toxicity during IT. We aimed to describe CV events (CVE)occurring during IT and to identify clinical, hematological and molecular risk factors of such events. Methods: Two hundred and twenty-four patients of 18 years or more (median age 61 (51;67) years, 58% males), treated with ITbetween 2014 and 2021 were enrolled in this study. Two hundred and one (90%) received an anthracycline-based IT, the others received gemtuzumab ozogamicin as part of a clinical protocol research. Survival from the time from initiation of IT until death or until the initiation of the second course of therapy (either salvage regimen in case of primary refractory or relapsed AML, or intensive consolidation therapy in case of response) was considered. The primary endpoint was the time to occurrence of the first CVE after IT initiation, with death as a competing event. Multivariate analysis included significant covariate, identified by univariate models among initial characteristics and occurrence of infection (coded as time dependent covariate). Results: Hematological characteristics were as follows: European LeukemiaNet (ELN) 2022 risk of myelodysplastic neoplasm (MDS)/AML was low, intermediate and adverse in 13%, 29% and 58% of patients respectively. Main mutations encounters were: DNMT3A, FLT3, NPM1, TET2, NRAS, RUNX1, ASXL1, IDH2, PTPN11, BCOR, SRSF2, WT1 and TP53. Main CV risk factors were tobacco (36%), arterial hypertension (35%), obesity (24%), hyperlipidemia (22%), diabetes mellitus (11%). Baseline left ventricular ejection fraction (assessed by transthoracic echocardiography) was &amp;gt;45% in all patients, &amp;gt;55% in 95% of patients. Seventy-five patients (33%) presented a CVE during IT. Eighty-six percent of CVE were severe (grade 3 or more). Patients presenting CVE during IT were significantly older (p=0.02) and presented more often a past history of dilated cardiomyopathy (p=0.04), arterial hypertension (p=0.005) or dyslipidemia (p=0.005). At baseline, CVE patients presented a greater left auricle volume (p=0.005), higher tricuspid regurgitation grade (p=0.01), and more often a right ventricular dilatation or a significative valvopathy (respectively p=0.01 and p=0.03). There was no difference in CVE occurrence between patients treated with and without anthracyclin (p=0.2). Competing risk models identified the following adverse characteristic for the risk of first CVE, namely the occurrence of the first infectious event (Hazard ratio [HR]= 2.43, p=0.005), TP53 mutation (HR=1.79, p=0.04). No other clinical characteristics nor mutation (including TET2 and DNMT3A) were identified. Multivariate analyses demonstrated that TP53 mutation (HR=1.78, p=0.04) and occurrence of infection (HR=2.29, p=0.008) retained independent prognostic value, see Table 1. In a response stratified model, only TP53 mutation was a risk factor of first CVE (HR=2.46, p=0.008). Conclusions: CVE occurred in 33% of patients during IT and were severe. The major adverse role of onset of infection for CVE occurrence after IT could overcome the prognostic value of mutations usually associated with CV risk in the healthy population (i.e. TET2, DNMT3A, ASXL1, ...). TP53 mutation was the only molecular abnormality associated with CVE, in agreement with the increased risk of doxorubicin-induced cardiac toxicity in a mouse model of TP53 clonal hematopoiesis developed by Sano et al. These results suggest that TP53 mutated patients could benefit from careful CV monitoring and optimization of primary prevention treatment.

Fecal Microbiota Transplantation in Mice Exerts a Protective Effect Against Doxorubicin-Induced Cardiac Toxicity by Regulating Nrf2-Mediated Cardiac Mitochondrial Fission and Fusion.

Aims: The relationship between the gut microbiota and cardiovascular system has been increasingly clarified. Fecal microbiota transplantation (FMT), used to improve gut microbiota, has been applied clinically for disease treatment and has great potential in combating doxorubicin (DOX)-induced cardiotoxicity. However, the application of FMT in the cardiovascular field and its molecular mechanisms are poorly understood. Results: During DOX-induced stress, FMT alters the gut microbiota and serum metabolites, leading to a reduction in cardiac injury. Correlation analysis indicated a close association between serum metabolite indole-3-propionic acid (IPA) and cardiac function. FMT and IPA achieve this by facilitating the translocation of Nfe2l2 (Nrf2) from the cytoplasm to the nucleus, thereby activating the expression of antioxidant molecules, reducing reactive oxygen species production, and inhibiting excessive mitochondrial fission. Consequently, mitochondrial function is preserved, leading to the mitigation of cardiac injury under DOX-induced stress. Innovation: FMT has the ability to modify the composition of the gut microbiota, providing not only protection to the intestinal mucosa but also influencing the generation of serum metabolites and regulating the Nrf2 gene to modulate the balance of cardiac mitochondrial fission and fusion. This study comprehensively demonstrates the efficacy of FMT in countering DOX-induced myocardial damage and elucidates the pathways linking the microbiota and the heart. Conclusion: FMT alters the gut microbiota and serum metabolites of recipient mice, promoting nuclear translocation of Nrf2 and subsequent activation of downstream antioxidant molecule expression, while inhibiting excessive mitochondrial fission to preserve cardiac integrity. Correlation analysis highlights IPA as a key contributor among differentially regulated metabolites.

Galectin-3 contributes to acute cardiac dysfunction and toxicity by increasing oxidative stress and fibrosis in doxorubicin-treated mice

BackgroundDoxorubicin (DOX) leads to cardiovascular toxicity through direct cardiomyocyte injury and inflammation. We aimed to study the role of Galectin-3 (Gal-3), a β-galactosidase binding lectin associated with inflammation and fibrosis in DOX-induced acute cardiotoxicity in mice. MethodsMale C57 and Gal-3 knockout (KO) mice were given a single dose of DOX (15 mg/kg, i.p) or placebo. Serum creatine phosphokinase (CPK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and cardiac thiobarbituric acid-reactive substance (TBARS) were measured at 3 days to assess cardiac injury and oxidative stress. Cardiac remodeling and function were studied by echocardiography and catheterization at 7 days. Myocardial fibrosis was quantified in picrosirius red stained slices. ResultsAbsence of Gal-3 tended to reduce the mortality after DOX. DOX significantly increased CPK, LDH, AST and TBARS while treated Gal-3 KO mice showed reduced injury and oxidative stress. After 7 days, adverse remodeling, fibrosis and dysfunction in treated-C57 mice were severely affected while those effects were prevented by absence of Gal-3. ConclusionIn summary, genetic deletion of Gal-3 prevented cardiac damage, adverse remodeling and dysfunction, associated with reduced cardiac oxidative stress and fibrosis. Understanding the contribution of GAL-3 to doxorubicin-induced cardiac toxicity reinforces its potential use as a therapeutic target in patients with several cancer types.

Protective Effect of Omega-3 and the Potential of Toll-like Receptor Gene Expression in Rats with Doxorubicin-induced Cardiac Toxicity

Despite the clinical signs of doxorubicin (DOX)-induced cardiomyopathy, the mechanisms underlying DOX-induced cardiac damage are unknown. Toll-like receptors (TLRs) allow cardiomyocytes to respond to either endogenous or external signals, both of which have the potential to alter the pathophysiological responses to dilated cardiomyopathy. Omega-3 (OMG-3) precursors are highly active metabolites with numerous therapeutic benefits in the prevention and/or treatment of a variety of diseases. Thus, this study was aimed at evaluating the preventive effect of omega-3 on rats suffering from acute DOX-induced cardiotoxicity associated with TLR gene expression. Thirty rats were divided into five equal groups; Group 1 received no treatment, Group 2 received doxorubicin (at a toxic dose of 20 mg/kg), and Groups 3-5 received doxorubicin (20 mg/kg) after receiving OMG-3 at various doses (100, 200, and 400 mg/kg/day, respectively) for 4 weeks. At the end of the experiment, blood samples were obtained from the heart. The real time polymerase chain reaction (RT-PCR) was used to assess TLR2 and TLR4 gene expression. TLR2 had a significantly (p&lt;0.01) elevated fold change in the DOX alone group (28.74+4.95), whereas TLR2 expression was significantly reduced in the OMG-3 pretreated groups (1.633+0.51, 0.733+0.13, and 0.709+0.16, respectively). TLR4 fold change in the DOX alone group was 8.57+1.22, whereas TLR4 expression was significantly reduced in the OMG-3 pretreated groups (100, 200, and 400 mg/kg) with values of 0.809+0.32, 0.852+0.50, and 0.272+0.16, respectively. The findings of this study revealed that OMG-3 decreased doxorubicin-induced cardiotoxicity and showed a significant cardioprotective effect by lowering TLR2 and TLR4 gene expression.

Synergistic impacts of Montelukast and Klotho against doxorubicin-induced cardiac toxicity in Rats.

Doxorubicin (DOX) is a powerful antitumor agent with a well-known cardiaotoxic side effects. In the current study, the ameliorative combined impacts of montelukast (Mont) and Klotho against doxorubicin-induced cardiac toxicity were examined. Fifty-six adult male rats (2months age and weighting 150-200 g) were grouped into 7 groups (8 rats per group). Animals received doxorubicin alone or in combination with either Mont or Klotho. After 2weeks of treatments, serum samples were examined to assess the changes in cardiac activity biomarkers such as LDH, CK-MB, cardiac troponin-I (cTn-I), and heart fatty acid binding protein (H-FABP). Serum changes of IL-6, inducible nitric oxide synthase (iNOS), and caspase-3 levels were assayed. The oxidative stress biomarkers such as total antioxidant capacity (TAC) and inflammatory (rat IL-1β and rat TNF-α,) and anti-inflammatory (rat IL-10) cytokines were examined. Heart histology and transforming growth factor-β1 (TGF-β1) immunoreactivity were measured. DOX induced cardiomyopathy, which was reflected by the increases in all examined cardiac parameters. Real-time PCR confirmed that DOX upregulated the expression of TNF-α and IL-1β and decreased the expression of IL-10. Moreover, DOX showed marked elevation in the ST segment T wave complex, causing profound tachycardia. Heart histology assessments showed cardiac cell necrosis, inflammatory cell infiltration, interstitial congestion, and increased TGF-β1 immunoreactivity. Montelukast and Klotho administration ameliorated all the altered parameters when administered alone or in combination to DOX-intoxicated rats. Klotho was more effective compared with montelukast in terms of reductions in heart rate, ST segment T wave complex elevation, cardiac enzymes (lactate dehydrogenase; LDH, creatine kinase-MB; CK-MB, cardiac troponin I; cTn-I, heart fatty acid binding protein; H-FABP) cardiac histology, and caspase-3 levels and increases in TAC activity. Montelukast was more effective in reducing serum levels of IL6 and iNOS, expression of TNF-α and IL-1β, and the upregulation of IL-10 expression. The co-administration of both drugs led to significantly more synergistic results in terms of reducing cardiac toxicity. In conclusion, montelukast and Klotho either alone or in combination were confirmed to be effective in suppressing DOX-induced cardiac toxicity in rats.

Cardioprotective Effect of Rheum turkestanicum Against Doxorubicin-Induced Toxicity in Rats.

Background: Doxorubicin as an anti-cancer drug causes cardiotoxicity, limiting its tolerability and use. The mechanism of toxicity is due to free radical production and cardiomyocytes injury. This research evaluated Rheum turkestanicum (R.turkestanicum) extract against doxorubicin cardiotoxicity due to its considerable in vitro antioxidant activity. Methods: Male Wistar rats received 2.5 mg/kg doxorubicin intraperitoneally every other day for 2 weeks to create an accumulative dose. R. turkestanicum was administrated at a dose of 100 and 300 mg/kg intraperitoneally from the second week for 7 days. On the 15th day, the animals were anesthetized and blood was collected from cardiac tissue for evaluation of alanine aminotransferase (ALT), cardiac muscle creatinine kinase (CK-MB), troponin T (cTn-T), lactate dehydrogenase (LDH), and B-type natriuretic peptide brain natriuretic peptide. A cardiac homogenate was also collected to determine superoxide dismutase (SOD), catalase Catalase Activity, malondialdehyde (MDA), and thiols. Histopathology was also performed. Results: Doxorubicin increased all cardiac enzymes and malondialdehyde, correlating with a reduction in SOD, catalase, and thiols. Histopathology revealed extracellular edema, moderate congestion, and hemorrhage of foci. In contrast, administration of R. turkestanicum ameliorated these doxorubicin-induced pathophysiological changes. Conclusion: This study revealed that the extract ameliorated doxorubicin-induced cardiac toxicity via modulation of oxidative stress-related pathways. Liquid chromatography-mass spectrometry analysis of R. turkestanicum indicated several components with potent pharmacological properties.

Synergistic Therapeutic Effect of L-Carnitine Nanoparticles and Moringa Oleifera Against Doxorubicin Induced Cardiac Toxicity in Male Rats: Biochemical and Histological Study

Doxorubicin (DOX) is a powerful chemotherapeutic agent. However, dose-dependent cardiotoxicity may limit its clinical applicability. This study was directed to explore the possible therapeutic effects of L-Carnitine Nanoparticles (LCNPs) and Moringa Oleifera extract (MO) against doxorubicin-induced cardiac toxicity in male rats. Fifty rats were allocated into two main groups: the first served as a normal control group (con.) (n=10). The remaining 40 rats were given doxorubicin at a cumulative dose of 20 mg/kg b. wt. to induce cardiotoxicity. The Dox-treated rats were subdivided into 4 groups (n = 10/group) to be orally administered with 1) 0.9% normal saline; 2) MO at 400 mg /kg, b. wt./day; 3) LCNPs at 50 mg/kg b. wt./ day for four weeks; 4) MO+LCNPs group as previously indicated doses. The results demonstrated that DOX treatment raised MDA, NO, HO-1, and NF-kB levels while decreasing TAC activity. In addition to increased serum cardiac levels of CRP, CK, LDH, ALT, and Troponin-1 and Endothelin-1. LCNPs or MO treatment alleviated these changes. Whereas co-administration of LCNPs and MO reversed all these parameters. DOX treatment caused severe histopathological alterations in the cardiac tissues, corrected by LCNPs and MO treatment. In conclusion, these data imply that treating with LCNPs and MO in combination provides greater cardioprotection against DOX-induced cardiotoxicity in rats via repressing oxidative stress and boosting antioxidant status.

Fluvastatin alleviates doxorubicin-induced cardiac and renal toxicity in rats via regulation of oxidative stress, inflammation, and apoptosis associated genes expressions

Doxorubicin (DOXO) is a cytostatic agent used in the chemotherapy protocol of several cancers for more than 40 years, but usage of this drug in cancer treatment has been limited due to severe renal and cardiac tissue toxicities that may result in death in patients. Fluvastatin (FV) is a fully synthetic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor used as a cholesterol-lowering agent in patients with hypercholesterolemia. Previous studies revealed that FV also exhibits antioxidant, anti-inflammatory, and antitumor activity. Additionally, our previous study indicated that FV exerts a prophylactic effect on DOXO-induced testicular toxicity by preventing lipid peroxidation, supporting the antioxidant system, and regulating the blood-testis barrier-associated genes expression. Herein, we purposed to evaluate the possible therapeutic and the protective effects of FV on the DOXO-induced cardiac and renal toxicitiy model by histochemical, immunohistochemical, biochemical, and real-time polymerase chain reaction (real-time PCR) analyses. Results point out protective use of FV exerts a beneficial effect by repressing lipid peroxidation and by regulating the inducible nitric oxide synthase (iNOS), nitric oxide synthase endothelial (eNOS), nuclear factor kappa-B (NF-κB), and Caspase-3 (Casp3) protein and mRNA expressions, which play an important role in mediating DOXO-induced renal and cardiac toxicity mechanisms. In conclusion, FV may be a candidate agent for the prevention of renal and cardiac toxicities in cancer patients receiving DOXO chemotherapy.

Omega 3 fatty acids can reduce early doxorubicin‐induced cardiotoxicity in children with acute lymphoblastic leukemia

Omega 3 polyunsaturated fatty acids are dietary factors with several beneficial cardiovascular effects. This study aimed to assess the possible protective effect of omega 3 fatty acids on early doxorubicin-induced cardiac toxicity in children with acute lymphoblastic leukemia (ALL). Sixty children of newly diagnosed ALL were randomized into two groups: group I (n=30) who received omega 3 fatty acids 1000mg/day for 6months in addition to their usual protocol of chemotherapy including doxorubicin; and group II (n=30) who received their usual doxorubicin protocol during the period from February 2020 till August 2021. Echocardiographic examinations were performed before and after the treatment. Glutathione, malondialdehyde (MDA), superoxide dismutase (SOD), troponin I, creatine kinase MB (CK-MB), and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured also before and after omega 3 treatment. After 6months of omega 3 administration, group I had a significantly lower MDA level and a significantly higher glutathione and SOD levels than group II. Similarly, the levels of troponin I, CK-MB, and NT-proBNP were significantly high in group II, whereas they were unchanged in group I after treatment. Similarly, systolic function (presented with peak mitral annular systolic velocity and two-dimensional global longitudinal strain) of the heart was preserved in omega 3-treated patients, unlike the control group that showed significant impairment of left ventricular function after 6months. Omega 3 fatty acids may decrease early cardiac injury and doxorubicin-induced cardiotoxicity in children with ALL.

The Potential protective role of astaxanthin on doxorubicin-induced cardiac toxicity in rats

Abstract Background and Aim of Work Doxorubicin (DOX) is one of the most commonly used effective anticancer drugs, through its inhibition of topoisomerase II, DNA replication and repair. In addition, DOX leads to generation of semiquinone free radicals and oxygen free radicals which attack DNA and oxidize DNA bases. However, the clinical use of doxorubicin is limited by its adverse effects such as cardiotoxicity, which is acute and occurs within 2-3 days of its administration. Recently, the potential health benefits of Astaxanthin were investigated, however, the protective effect of astaxanthin supplementation on cardiac dysfunction induced by Doxorubicin is not clearly investigated. The aim of the present study is directed to investigate the possible role of astaxanthin (xanthophyll carotenoid) in protection against DOX- induced cardiac toxicity, and to elucidate the underlying mechanism(s). Materials and Methods Animals used were 47 adult male albino rats, which were randomly allocated into four groups. Control group(C): received 0.1ml/100gm BW i.p. saline injections for 7 successive days. DOX-treated group: received 0.1ml/100gm BW i.p. saline injections for 7 successive days, followed by a single i.p. injection of DOX, 20 mg/kg i.p. on the 7th day. ATX-treated group: received 40mg/kg/day BW i.p. ATX injections for 7 successive days. ATX+DOX treated group: received 40mg/kg/day BW i.p. ATX injections for 7 successive days, followed by a single i.p. injection of DOX, 20 mg/kg i.p. on the 7th day. At the end of the study, the overnight fasted rats were subjected to final arterial blood pressure measurement. Rats were then weighed and anaesthetized with 40 mg/kg B.W i.p. thiopental sodium. Then, ECG was recorded, blood samples were collected from abdominal aorta and centrifuged. The resulting plasma was used for measurement of plasma cardiac Troponin I (cTnI) and plasma Cytochrome C. The heart was subjected to In vitro study of isolated hearts perfused in langendorff preparation. Hearts and ventricles were weighed. The left ventricle was then stored at -80οC for later determination of cardiac tissue iron. Statistical Analysis was made using 1-way ANOVA for difference between means of different groups. Ethics Committee The study protocol was approved by the Research Ethical Committee of Faculty o fMedicine Ain Shams University (Reference No. FWA00017585). Results The systolic blood pressure was increased significantly in the DOX treated group compared to the control group. All of the systolic, diastolic and mean arterial blood pressures were significantly decreased in the ATX +DOX treated group compared to the DOX treated group. Heart rate was significantly increased in the ATX +DOX treated group compared to the control group, and compared to the DOX treated group. PT and PT/LVW were significantly increased in the ATX +DOX group compared to both of the DOX group and the control group. In addition, PT and PT/LVW were significantly increased in the ATX-treated group compared to the DOX group. The TPT was prolonged in the DOX group compared to the control group and this prolongation was statistically significant in pre-ischemia and 5 minutes after reperfusion of the isolated hearts, and was significantly shortened in the ATX-treated group and ATX +DOX group compared to the DOX. Also, TPT was significantly shortened in the ATX-treated and in the in the ATX +DOX groups compared to the control group. HRT was significantly prolonged in the DOX group compared to the control group. However, HRT was significantly shortened in the ATX-treated and ATX +DOX groups compared to the DOX group, and in the ATX +DOX group compared to the control group. The MFR and MFR/LVW were significantly decreased in the DOX group compared to the control group. However, the MFR was significantly increased in each of the ATX-treated group and ATX +DOX group when each was compared to the DOX group. Moreover, MFR was significantly increased in the ATX +DOX group compared to the control group. Each of plasma cardiac Troponin, plasma Cytochrome C and Cardiac Tissue Iron were significantly increased in the DOX group compared to the control group, and all were significantly decreased in the ATX-treated group when compared to DOX group, and in the ATX +DOX group when compared to the DOX group. No significant changes were detected in body weight, heart weights and ECG parameters between the different studied groups. Conclusion Doxorubicin produces acute cardiotoxic effects and impairs systolic and diastolic cardiac functions, which is due to increased oxidative stress, mitochondrial instability and iron accumulation in the cardiac tissue. Astaxanthin exerts a major cardioprotective activities against DOXinduced cardiotoxicity, probably due to its major antioxidant and iron chelation properties.

Normal tissue and tumor microenvironment adaptations to aerobic exercise enhance doxorubicin anti-tumor efficacy and ameliorate its cardiotoxicity in retired breeder mice.

Aerobic exercise is receiving increased recognition in oncology for its multiple purported benefits. Exercise is known to induce physiologic adaptations that improve patient quality-of-life parameters as well as all-cause mortality. There also is a growing body of evidence that exercise may directly alter the tumor microenvironment to influence tumor growth, metastasis, and response to anticancer therapies. Furthermore, the physiologic adaptations to exercise in normal tissues may protect against treatment-associated toxicity and allow for greater treatment tolerance. However, the exercise prescription required to induce these beneficial tumor-related outcomes remains unclear. This study characterized the aerobic adaptations to voluntary wheel running in normal tissues and the tumor microenvironment. Female, retired breeder BALB/c mice and syngeneic breast adenocarcinoma cells were utilized in primary tumor and metastasis models. Aerobic exercise was found to induce numerous adaptations across various tissues in these mice, although primary tumor growth and metastasis were largely unaffected. However, intratumoral hypoxia and global metabolism were altered in the tumors of exercising hosts relative to non-wheel running controls. Doxorubicin chemotherapy also was found to be more efficacious at delaying tumor growth with adjuvant aerobic exercise. Additionally, doxorubicin-induced cardiac toxicity was ameliorated in exercising hosts relative to non-wheel running controls. Taken together, these data suggest that the normal tissue and tumor microenvironment adaptations to aerobic exercise can improve doxorubicin efficacy while simultaneously limiting its toxicity.

Anti-Inflammatory and Antioxidative Effects of Sumatriptan Against Doxorubicin-Induced Cardiotoxicity in Rat

The clinical use of doxorubicin as a potent chemotherapeutic agent is limited due to its dose-dependent cardiotoxicity. Oxidative stress and inflammatory pathways have a pivotal role in doxorubicin-induced cardiotoxicity. Sumatriptan, a 5-hydroxytryptamine (5-HT)1B/1D agonist that is mainly used to relieve migraine pain, has suggested exerting protective effects in numerous pathological conditions through antiinflammatory properties. The aim of the present study was to investigate the effects of sumatriptan on doxorubicin-induced cardiotoxicity and the contribution of anti-inflammation and antioxidative responses. Cardiotoxicity was induced by the administration of doxorubicin three times a week (2.5 mg/kg i.p) for two consecutive weeks on male rats. The animals were divided into four groups, including Control, Sumatriptan (0.1 mg/kg) received group, doxorubicin received group, and Doxorubicin+Sumatriptan (0.1 mg/kg) received group. Sumatriptan was administered 30 min before every injection of doxorubicin. On the last day of the second week, the body weight, mortality rate, electrocardiogram (ECG) and histopathological changes, cardiac inotropic study, and biochemical factors were evaluated. The loss of body weight, mortality rate, ECG parameters, reduction of papillary muscle contractility force as well as histopathological scores following administration of doxorubicin indicated severe cardiac damage. However, treatment with sumatriptan inhibited the functional and structural impairment induced by doxorubicin. In addition, sumatriptan could significantly reduce cardiac tissue levels of malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-α), which were increased in the doxorubicin-treated rats. This study illustrated the protective effects of sumatriptan on decreasing doxorubicin-induced cardiac toxicity and mortality rate in part through inhibition of inflammatory and oxidative stress pathways.

Cytoprotective Effect of Vitamin D on Doxorubicin-Induced Cardiac Toxicity in Triple Negative Breast Cancer.

Background: Doxorubicin (Dox) is a first-line treatment for triple negative breast cancer (TNBC), but its use may be limited by its cardiotoxicity mediated by the production of reactive oxygen species. We evaluated whether vitamin D may prevent Dox-induced cardiotoxicity in a mouse TNBC model. Methods: Female Balb/c mice received rodent chow with vitamin D3 (1500 IU/kg; vehicle) or chow supplemented with additional vitamin D3 (total, 11,500 IU/kg). the mice were inoculated with TNBC tumors and treated with intraperitoneal Dox (6 or 10 mg/kg). Cardiac function was evaluated with transthoracic echocardiography. The cardiac tissue was evaluated with immunohistochemistry and immunoblot for levels of 4-hydroxynonenal, NAD(P)H quinone oxidoreductase (NQO1), C-MYC, and dynamin-related protein 1 (DRP1) phosphorylation. Results: At 15 to 18 days, the mean ejection fraction, stroke volume, and fractional shortening were similar between the mice treated with vitamin D + Dox (10 mg/kg) vs. vehicle but significantly greater in mice treated with vitamin D + Dox (10 mg/kg) vs. Dox (10 mg/kg). Dox (10 mg/kg) increased the cardiac tissue levels of 4-hydroxynonenal, NQO1, C-MYC, and DRP1 phosphorylation at serine 616, but these increases were not observed with vitamin D + Dox (10 mg/kg). A decreased tumor volume was observed with Dox (10 mg/kg) and vitamin D + Dox (10 mg/kg). Conclusions: Vitamin D supplementation decreased Dox-induced cardiotoxicity by decreasing the reactive oxygen species and mitochondrial damage, and did not decrease the anticancer efficacy of Dox against TNBC.

TP53-mediated therapy-related clonal hematopoiesis contributes to doxorubicin-induced cardiomyopathy by augmenting a neutrophil-mediated cytotoxic response.

Therapy-related clonal hematopoiesis (t-CH) is often observed in cancer survivors. This form of clonal hematopoiesis typically involves somatic mutations in driver genes that encode components of the DNA damage response and confer hematopoietic stem and progenitor cells (HSPCs) with resistance to the genotoxic stress of the cancer therapy. Here, we established a model of TP53-mediated t-CH through the transfer of Trp53 mutant HSPCs to mice, followed by treatment with a course of the chemotherapeutic agent doxorubicin. These studies revealed that neutrophil infiltration in the heart significantly contributes to doxorubicin-induced cardiac toxicity and that this condition is amplified in the model of Trp53-mediated t-CH. These data suggest that t-CH could contribute to the elevated heart failure risk that occurs in cancer survivors who have been treated with genotoxic agents.

Cardioprotective Effect of Quercetin and Sitagliptin in Doxorubicin-Induced Cardiac Toxicity in Rats.

ObjectiveA previous study revealed a pronounced protective effect of combining quercetin (QC) with sitagliptin (STN) in testicular tissue. Accordingly, this study was designed to evaluate the cardioprotective effects of QC and STN each alone or in combination in doxorubicin (DOX)-induced cardiotoxicity in the rats.MethodologyThirty male adult Wistar rats were divided into five groups: the first group (control) treated with sodium chloride, the second group treated with DOX (3 mg/kg I.P. injection), the third group treated with DOX with a combination of QC (80 mg/kg), and STN (10 mg/kg), the fourth group treated with DOX and QC and the fifth group treated with DOX and STN. Blood was collected on day 22 and used for assessment of serum troponin, lactate dehydrogenase (LDH), creatine phosphokinase (CPK), total lipid profile, C-reactive protein (CRP), and total antioxidant capacity (TAOC). Atherogenic indices were also calculated. Cardiac tissue was sent for histopathological analysis.ResultsDOX produced a significant increase in the level of troponin, LDH, CKP, CRP, total cholesterol (TC), low-density lipoprotein (LDL), triglycerides (TG), and atherogenic index of plasma; and significantly decreased TAOC. The combination of quercetin and sitagliptin was more effective than each treatment alone in restoring the level of troponin, LDH, CKP, CRP, Cholesterol, LDL, TG, atherogenic index of plasma and significantly increased TAOC compared to DOX treated group. The histopathological finding also supports the biochemical results.ConclusionThe study revealed the cardioprotective effects of the combination of QC and STN which could be attributed to the additive effects of this combination through antioxidant, anti-inflammatory, lipid lowering and anti-atherogenic activities; suggesting it as a good therapeutic candidate to be tested in the clinical setting.