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1.  UNCOUPLING PROTEIN DOWNREGULATION IN DOXORUBICIN INDUCED HEART FAILURE IMPROVES MITOCHONDRIAL COUPLING BUT INCREASES REACTIVE OXYGEN SPECIES GENERATION 
Cancer chemotherapy and pharmacology  2010;67(6):1381-1388.
PURPOSE
Doxorubicin-based chemotherapy is limited by the development of dose-dependent left ventricular dysfunction and congestive heart failure caused by reactive oxygen species (ROS). Uncoupling proteins (UCP) can inhibit mitochondrial ROS production as well as decrease myocyte damage from exogenous ROS. Prior studies have shown that cardiac UCP2 and UCP3 mRNA expression is decreased with acute doxorubicin treatment. However, the expression of UCP protein in hearts with doxorubicin cardiotoxicity and the resultant changes in mitochondrial function and oxidant stress have not been determined.
METHODS
Heart failure was induced in Sprague-Dawley rats with intraperitoneal injections of doxorubicin (2 mg/kg t.i.w., total dose: 18 mg/kg). Mitochondria were isolated from mice receiving doxorubicin or saline injections for determination of UCP2 and UCP3 expression. In addition, mitochondrial respiration, ATP synthesis and ROS production were determined.
RESULTS
Doxorubicin-induced heart failure was associated with significant decreases in UCP2 and UCP3 protein expression compared to nonfailing hearts (p<0.05). While the rates of state 3 and state 4 respiration and ATP synthesis were lower in mitochondria isolated from failing hearts, the respiratory control ratio was 15% higher (p<0.05) and the ratio of ATP production to oxygen consumption was 25% higher (p<0.05) in mitochondria from failing hearts, indicating greater coupling between citric acid cycle flux and mitochondrial ATP synthesis. However, the decrease in UCP expression was associated with 50% greater mitochondrial ROS generation (p<0.05).
CONCLUSIONS
Downregulation of myocardial UCP2 and UCP3 in the setting of doxorubicin-induced heart failure is associated with improved efficiency of ATP synthesis, which might compensate for abnormal energy metabolism. However, this beneficial effect is counterbalanced by greater oxidant stress.
doi:10.1007/s00280-010-1441-7
PMCID: PMC3051028  PMID: 20809120
cardiotoxicity; mitochondria; reactive oxygen species; energetics
2.  Pre-treatment with ACE Inhibitor Attenuates Doxorubicin Induced Cardiomyopathy via Preservation of Mitochondrial Function 
Aims
Doxorubicin is a widely used chemotherapy drug, but its application is associated with cardiotoxicity. Free radical generation and mitochondrial dysfunction are thought to contribute to doxorubicin-induced cardiac failure. Angiotensin-converting enzyme (ACE) inhibitors are commonly used as cardioprotective agents and have recently been shown in clinical studies to be efficacious in the prevention of anthracycline induced heart failure. Here we evaluated a mechanism for these protective effects by testing the ability of the ACE inhibitor enalapril to preserve mitochondrial function in a model of chronic doxorubicin treatment in rats.
Methods
Sprague Dawley rats were divided into three groups and followed for a total of 10 weeks: a) control-untreated, b) Doxorubicin treated (Dox), and c) Doxorubicin + Enalapril treated (DE). Doxorubicin was administered via intraperitoneal injection at weekly intervals from week 2 through week 7. Enalapril was administered in the drinking water of the DE group for the study duration.
Results
Doxorubicin treatment produced a significant loss in left ventricular contractility (P< 0.05), decrease in mitochondrial function via impairment of state-3 respiration, decrease in the cytosolic fraction of ATP, and up-regulation of free radical production. Enalapril significantly attenuated the decrease in percent fractional shortening (P< 0.05) and prevented the doxorubicin-associated reduction in respiratory efficiency and cytosolic ATP content (P< 0.05). Importantly, enalapril also abolished the robust doxorubicin-induced increase in free radical formation.
Conclusions
Administration of enalapril attenuates doxorubicin-induced cardiac dysfunction via preservation of mitochondrial respiratory efficiency and reduction in doxorubicin-associated free radical generation.
doi:10.1016/j.jtcvs.2010.07.097
PMCID: PMC3173512  PMID: 21094500
doxorubicin; mitochondria; cardiotoxicity; ACE inhibitor; free radicals
3.  The Redox Imbalance and the Reduction of Contractile Protein Content in Rat Hearts Administered with L-Thyroxine and Doxorubicin 
Oxidative stress and disorders in calcium balance play a crucial role in the doxorubicin-induced cardiotoxicity. Moreover, many cardiotoxic targets of doxorubicin are regulated by iodothyronine hormones. The aim of the study was to evaluate effects of tetraiodothyronine (0.2, 2 mg/L) on oxidative stress in the cardiac muscle as well as contractility and cardiomyocyte damage markers in rats receiving doxorubicin (1.5 mg/kg) once a week for ten weeks. Doxorubicin was administered alone (DOX) or together with a lower (0.2T4 + DOX) and higher dose of tetraiodothyronine (2T4 + DOX). Two groups received only tetraiodothyronine (0.2T4, 2T4). Coadministration of tetraiodothyronine and doxorubicin increased the level of lipid peroxidation products and reduced RyR2 level when compared to untreated control and group exposed exclusively to doxorubicin. Insignificant differences in SERCA2 and occasional histological changes were observed. In conclusion, an increase of tetraiodothyronine level may be an additional risk factor of redox imbalance and RyR2 reduction in anthracycline cardiotoxicity.
doi:10.1155/2012/681367
PMCID: PMC3317061  PMID: 22530076
4.  Doxorubicin Toxicity can be Ameliorated during Antioxidant L-Carnitine Supplementation 
Doxorubicin is an antibiotic broadly used in treatment of different types of solid tumors. The present study investigates whether L-carnitine, antioxidant agent, can reduce the hepatic damage induced by doxorubicin. Male Wistar albino rats were divided into six groups: group 1 was intraperitoneal injected with normal saline for 10 consecutive days; group 2, 3 and 4 were injected every other day with doxorubicin (3 mg/kg, i.p.), to obtain treatments with cumulative doses of 6, 12 and 18 mg/kg. The fifth group was injected with L-carnitine (200 mg/kg, i.p.) for 10 consecutive days and the sixth group was received doxorubicin (18 mg/kg) and L-carnitine (200 mg/kg). High cumulative dose of doxorubicin (18 mg/kg) significantly increases the biochemical levels of alanine transaminase, alkaline phosphatase, total bilirubin, thiobarbituric acid reactive substances (TBARs), total nitrate/nitrite (NOx) p < 0.05 and decrease in glutathione (GSH ), superoxide dismutase (SOD), glutathione peroxidase (GSHP x), glutathione-s-transferase (GST), glutathione reductase (GR) and catalase (CAT) activity p < 0.05. The effect of doxorubicin on the activity of antioxidant genes was confirmed by real time PCR in which the expression levels of these genes in liver tissue were significantly decrease compared to control p < 0.05. Interestingly, L-carnitine supplementation completely reversed the biochemical and gene expression levels induced by doxorubicin to the control values. In conclusion, data from this study suggest that the reduction of antioxidant defense during doxorubicin administration resulted in hepatic injury could be prevented by L-carnitine supplementation by decreasing the oxidative stress and preserving both the activity and gene expression level of antioxidant enzymes.
doi:10.4161/oxim.3.6.14416
PMCID: PMC3154045  PMID: 21307642
5.  Interrelation between Expression of ADAM 10 and MMP 9 and Synthesis of Peroxynitrite in Doxorubicin Induced Cardiomyopathy 
Biomolecules & Therapeutics  2013;21(5):371-380.
Doxorubicin is still main drug in chemotherapy with limitation of use due to adverse drug reaction. Increased oxidative stress and alteration of nitric oxide control have been involved in cardiotoxicity of doxorubicin (DOX). A Disintegrin And Metalloproteinase (ADAMs) are transmembrane ectoproteases to regulate cell-cell and cell-matrix interactions, but role in cardiac disease is unclear. The aim of this study was to determine whether DOX activates peroxynitrite and ADAM 10 and thus ADAM and matrix metalloproteinase (MMP) induce cardiac remodeling in DOX-induced cardiomyopathy. Adult male Sprague-Dawley rats were subjected to cardiomyopathy by DOX (6 times of 2.5 mg/kg DOX over 2-weeks), and were randomized as four groups. Then followed by 3, 5, 7, and 14 days after cessation of DOX injection. DOX-injected animals significantly decreased left ventricular fractional shortening compared with control by M-mode echocardiography. The expressions of cardiac nitrotyrosine by immunohistochemistry were significant increased, and persisted for 2 weeks following the last injection. The expression of eNOS was increased by 1.9 times (p<0.05), and iNOS was marked increased in DOX-heart compared with control (p<0.001). Compared to control rats, cardiac ADAM10- and MMP 9- protein expressions increased by 20 times, and active/total MMP 9 proteolytic activity showed increase tendency at day 14 after cessation of DOX injection (n=10, each group). DOX-treated H9C2 cell showed increased ADAM10 protein expression with dose-dependency (p<0.01) and morphometric changes showed the increase of ventricular interstitial, nonvascular collagen deposition. These data suggest that activation of cardiac peroxynitrite with increased iNOS expression and ADAM 10-dependent MMP 9 expression may be a molecular mechanism that contributes to left ventricular remodeling in DOXinduced cardiomyopathy.
doi:10.4062/biomolther.2013.034
PMCID: PMC3825201  PMID: 24244825
Doxorubicin; Cardiomyopathy; ADAM; MMP
6.  Desferrioxamine Attenuates Doxorubicin-Induced Acute Cardiotoxicity through TFG-β/Smad p53 Pathway in Rat Model 
Interaction of doxorubicin DOX with iron and the consequent generation of reactive oxygen species (ROS) is a major player in DOX-induced cardiomyopathy. Accordingly, this study has been initiated to investigate the preventive effect of the iron chelator, desferrioxamine (DFX), against DOX-induced acute cardiotoxicity in rats. Male Wistar albino rats were divided into four groups and were injected intraperitoneally (I.P.) with normal saline, a single dose of DOX (15 mg/kg), a single dose of DFX (250 mg/kg) and a combined treatment with DFX (250 mg/kg) 30 min prior to a single dose of DOX, (15 mg/kg). A single dose of DOX significantly increased mRNA expression of TGF-β, Smad2, Smad4, CDKN2A and p53 and significantly decreased Samd7 and Mdm2 mRNA expression levels. Administration of DFX prior to DOX resulted in a complete reversal of DOX-induced alteration in cardiac enzymes and gene expression to normal levels. Data from this study suggest that (1) DOX induces its acute cardiotoxicity secondary to increasing genes expression of TGF-β/Smad pathway. (2) DOX increases apoptosis through upregulation of CDKN2A and p53 and downregulation of Mdm2 gene expression. (3) The preventive effect of DFX against DOX-induced cardiotoxicity is mediated via the TGF-β1/Smad pathway.
doi:10.1155/2012/619185
PMCID: PMC3350848  PMID: 22619697
7.  Schisandrin B Prevents Doxorubicin-Induced Chronic Cardiotoxicity and Enhances Its Anticancer Activity In Vivo 
PLoS ONE  2011;6(12):e28335.
Background
To mitigate the cardiotoxicity of anthracycline antibiotics without compromising their anticancer activities is still an issue to be solved. We previously demonstrated that schisandrin B (Sch B) could protect against doxorubicin (Dox)-induced acute cardiotoxicity via enhancing cardiomyocytic glutathione redox cycling that could attenuate oxidative stress generated from Dox. In this study, we attempted to prove if Sch B could also protect against Dox-induced chronic cardiotoxicity, a more clinically relevant issue, without compromising its anticancer activity.
Methodology
Rat was given intragastrically either vehicle or Sch B (50 mg/kg) two hours prior to i.p. Dox (2.5 mg/kg) weekly over a 5-week period with a cumulative dose of Dox 12.5 mg/kg. At the 6th and 12th week after last dosing, rats were subjected to cardiac function measurement, and left ventricles were processed for histological and ultrastructural examination. Dox anticancer activity enhanced by Sch B was evaluated by growth inhibition of 4T1, a breast cancer cell line, and S180, a sarcoma cell line, in vitro and in vivo.
Principal Findings
Pretreatment with Sch B significantly attenuated Dox-induced loss of cardiac function and damage of cardiomyocytic structure. Sch B substantially enhanced Dox cytotoxicities toward S180 in vitro and in vivo in mice, and increased Dox cytotoxcity against 4T1 in vitro. Although we did not observe this enhancement against the implanted 4T1 primary tumor, the spontaneous metastasis to lung was significantly reduced in combined treatment group than Dox alone group.
Conclusion
Sch B is capable of protecting Dox-induced chronic cardiotoxicity and enhancing its anticancer activity. To the best of our knowledge, Sch B is the only molecule ever proved to function as a cardioprotective agent as well as a chemotherapeutic sensitizer, which is potentially applicable for cancer treatment.
doi:10.1371/journal.pone.0028335
PMCID: PMC3229562  PMID: 22164272
8.  Naproxen aggravates doxorubicin-induced cardiomyopathy in rats 
Indian Journal of Pharmacology  2010;42(1):44-49.
Background:
The repercussion of the heated dispute on cyclooxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drugs (NSAIDs) led to the national and international withdrawal of several of the recently introduced coxibs. Further debate and research have highlighted risks of the classical NSAIDs too. There is much controversy about the cardiovascular safety of a nonselective NSAID naproxen (NAP) and its possible cardioprotective effect.
Objectives:
The study was undertaken to determine the cardiovascular effects of NAP on doxorubicin-induced cardiomyopathy in rats.
Materials and Methods:
Male albino rats received a single i.p. injection of normal saline (normal control group) and doxorubicin (DOX) 15 mg/kg (toxic control group). Naproxen was administered alone (50 mg/kg/day, p.o.) and in combination with DOX and DOX + trimetazidine (TMZ) (10 mg/kg/day, p.o.) for 5 days after 24 h of DOX treatment. DOX-induced cardiomyopathy was assessed in terms of increased activities of serum lactate dehydrogenase (LDH), tissue thiobarbituric acid reactive substances (TBARS) and decreased activities of myocardial glutathione, superoxide dismutase and catalase, followed by transmission electron microscopy of the cardiac tissue.
Results:
Doxorubicin significantly increased oxidative stress as evidenced by increased levels of LDH and TBARS and decreased antioxidant enzymes levels. Both biochemical and electron microscopic studies revealed that NAP itself was cardiotoxic and aggravated DOX-induced cardiomyopathy and abolished the protective effect of TMZ in rats.
Conclusions:
This study indicates that NAP has the potential to worsen the situation in patients with cardiovascular disease. Therefore, it should be used cautiously in patients with compromised cardiac function.
doi:10.4103/0253-7613.62411
PMCID: PMC2885640  PMID: 20606837
Apoptosis; cardiomyopathy; enzyme (kinetics); free radicals; nonsteroidal anti-inflammatory drugs
9.  Cardioprotective effect of curcumin against doxorubicin-induced myocardial toxicity in albino rats 
Indian Journal of Pharmacology  2012;44(1):73-77.
Objectives:
To study the preventive role of curcumin against doxorubicin (Dox)-induced myocardial toxicity in rats.
Materials and Methods:
Cardiotoxicity was produced by cumulative administration of Dox (15 mg/kg for two weeks). Curcumin (200 mg/kg, po) was administered as pretreatment for two weeks and then for two alternate weeks with Dox. The general observations, mortality, histopathology, biomarker enzymes like lactate dehydrogenase (LDH) and creatine phosphokinase (CPK), biochemical parameters such as aspartate aminotransferase (AST) alanine aminotransferase (ALT) and alkaline phosphatase (ALP), antioxidant enzymes such as glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were monitored after three weeks of last dose.
Results:
The repeated administration of Dox induced cardiomyopathy associated with an antioxidant deficit and increased level biomarkers. Pretreatment with the curcumin significantly protected myocardium from the toxic effects of Dox by reducing the elevated level of biomarker enzymes like LDH and CPK and biochemical parameters such as AST, ALT and ALP back to normal. Curcumin increased the reduced level of GSH, SOD and CAT and decreased the elevated level of malondialdehyde (MDA) in cardiac tissue.
Conclusion:
The biochemical and histopathology reports support the cardioprotective effect of curcumin which could be attributed to antioxidant.
doi:10.4103/0253-7613.91871
PMCID: PMC3271544  PMID: 22345874
Antioxidant; cardiotoxicity; curcumin; doxorubicin; free radicals
10.  Cardiomyocyte death in doxorubicin-induced cardiotoxicity 
SUMMARY
Doxorubicin (DOX) is one of the most widely used and successful antitumor drugs, but its cumulative and dose-dependent cardiac toxicity has been the major concern of oncologists in cancer therapeutic practice for decades. With the increasing population of cancer survivals, there is a growing need to develop preventive strategies and effective therapies against DOX-induced cardiotoxicity, in particular, the late onset cardiomyopathy. Although intensive investigations on the DOX-induced cardiotoxicity have been continued for decades, the underlying mechanisms responsible for DOX-induced cardiotoxicity have not been completely elucidated. A rapidly expanding body of evidence supports that cardiomyocyte death by apoptosis and necrosis is a primary mechanism of DOX-induced cardiomyopathy and other types of cell death, such as autophagy and senescence/aging, may participate in this process. In this review, we will focus on the current understanding of molecular mechanisms underlying DOX-induced cardiomyocyte death, including the major primary mechanism of excess production of reactive oxygen species (ROS) and other recently discovered ROS-independent mechanisms. Different sensitivity to DOX-induced cell death signals between adult and young cardiomyocytes will also be discussed.
doi:10.1007/s00005-009-0051-8
PMCID: PMC2809808  PMID: 19866340
cardiomyocyte; doxorubicin; apoptosis; necrosis; autophagy
11.  Tirapazamine-Doxorubicin Interaction Referring to Heart Oxidative Stress and Ca2+ Balance Protein Levels 
Doxorubicin (DOX) causes long-term cardiomyopathy that is dependent on oxidative stress and contractility disorders. Tirapazamine (TP), an experimental adjuvant drug, passes the same red-ox transformation as DOX. The aim of the study was to evaluate an effect of tirapazamine on oxidative stress, contractile protein level, and cardiomyocyte necrosis in rats administered doxorubicin. Rats were intraperitoneally injected six times once a week with tirapazamine in two doses, 5 (5TP) and 10 mg/kg (10TP), while doxorubicin was administered in dose 1.8 mg/kg (DOX). Subsequent two groups received both drugs simultaneously (5TP+DOX and 10TP+DOX). Tirapazamine reduced heart lipid peroxidation and normalised RyR2 protein level altered by doxorubicin. There were no significant changes in GSH/GSSG ratio, total glutathione, cTnI, AST, and SERCA2 level between DOX and TP+DOX groups. Cardiomyocyte necrosis was observed in groups 10TP and 10TP+DOX.
doi:10.1155/2012/890826
PMCID: PMC3362211  PMID: 22666522
12.  Increased Beta2-Adrenoceptors in Doxorubicin-Induced Cardiomyopathy in Rat 
PLoS ONE  2013;8(5):e64711.
Background
The toxicity of doxorubicin, leading to an irreversible heart failure, limits its use as chemotherapeutic agent. The beneficial effects of early administration of β-blocker were reported in patients with heart failure due to doxorubicin, suggesting an important role of β-adrenoceptors (β-ARs). This study aimed to identify a putative target (β-AR and/or its effectors) at the early phase of a chronic doxorubicin-induced cardiomyopathy (Dox-CM) in a rat model.
Methodology
Dox-CM was induced by six doxorubicin injections (cumulative dose: 15 mg.kg−1) and validated by echocardiography and left ventricle (LV) catheterization. The β-AR protein expressions in LV were evaluated by western-blot at days 35 (d35) and 70 (d70) after the first doxorubicin injection. Ex vivo cardiac contractility (dP/dtmax, dP/dtmin) was evaluated on isolated heart in response to specific β-AR stimulations at d35.
Results
At d35, Dox-CM hearts were characterized by mild LV systolic and diastolic dysfunctions, which were exacerbated at d70. In Dox-CM hearts, β3-AR expression was only decreased at d70 (-37±8%). At d35, β1-AR expression was decreased by 68±6%, but ex vivo β1-AR function was preserved due to, at least in part, an increased adenylyl cyclase response assessed by forskolin. β2-AR expression was increased both at d35 (+58±22%) and d70 (+174±35%), with an increase of ex vivo β2-AR response at d35. Inhibition of Gi protein with pertussis toxin did not affect β2-AR response in Dox-CM hearts, suggesting a decoupling of β2-AR to Gi protein.
Conclusion
This study highlights the β1/β2-AR imbalance in early Dox-CM and reveals the important role that β2-AR/Gi coupling could play in this pathology. Our results suggest that β2-AR could be an interesting target at early stage of Dox-CM.
doi:10.1371/journal.pone.0064711
PMCID: PMC3669386  PMID: 23741376
13.  Doxorubicin-induced cardiotoxicity in adult Indian patients on chemotherapy 
Background:
Doxorubicin-induced cardiotoxicity is widely known to occur at cumulative doses exceeding 450 mg/m2. However, very few studies have reported incidence of cardiac dysfunction in patients on chemotherapy with lower cumulative doses. To the best of our knowledge, there is no study carried out so far that has reported the incidence of cardiac dysfunction in adult Indian patients receiving doxorubicin. This study was undertaken to determine the incidence of doxorubicin-induced cardiotoxicity by serial resting echocardiography in patients on chemotherapy and identify risk factors associated with cardiotoxicity.
Materials and Methods:
Patients that were started on doxorubicin-based chemotherapy in the period from January 2000 to June 2001 and had completed at least 300 mg/m2 cumulative dose were taken in the study. Electrocardiography, chest X-ray and echocardiography were done at baseline, at 300 mg/m2 and at 450 mg/m2 cumulative doses of doxorubicin. All patients were evaluated for the presence of the following risk factors: Age>70 years, female sex, preexisting cardiac disease, hypertension, chest wall irradiation, body mass index (BMI)<20 kg/m2 , Karnofsky performance status, combination chemotherapy with cyclophosphamide and presence of liver disease. Subclinical cardiac dysfunction was defined as ejection fraction fall greater than 10% on follow-up echocardiography.
Results:
Thirty patients satisfied the criterion for being considered for evaluation. One (3%) patient developed congestive cardiac failure, while 8 (27%) patients developed subclinical cardiac dysfunction. Concomitant use of cyclophosphamide significantly increased the risk of cardiac dysfunction (P = 0.048), while low BMI (<20 kg/m2) and preexisting cardiac disease showed a trend towards increased risk of cardiac dysfunction (P = 0.07 for both).
Conclusion:
Twenty-seven percent of the patients developed subclinical cardiac dysfunction in the cumulative dose range of 300-450 mg/m2 . This entails regular monitoring for cardiac dysfunction by echocardiography during treatment.
doi:10.4103/0971-5851.56329
PMCID: PMC2902208  PMID: 20668600
Doxurubicin; cardiotoxicity; echocardiographic monitoring
14.  Acute doxorubicin cardiotoxicity is associated with p53-induced inhibition of the mTOR pathway 
Circulation  2008;119(1):99-106.
Background
Doxorubicin (DOX) is used to treat childhood and adult cancer. DOX treatment is associated with both acute and chronic cardiotoxicity. The cardiotoxic effects of DOX are cumulative, limiting its chemotherapeutic dose. Free radical generation and p53-dependent apoptosis are thought to contribute to DOX-induced cardiotoxicity.
Methods and Results
Adult transgenic (MHC-CB7) mice expressing cardiomyocyte-restricted dominant-interfering p53 and their non-transgenic (NON-TXG) littermates were treated with DOX (20 mg/kg cumulative dose). NON-TXG mice exhibited reduced left ventricular (LV) systolic function (pre-DOX Fractional Shortening, FS, = 61 ± 2%, post-DOX FS = 45 ± 2%, mean +/- SEM, p<0.008), reduced cardiac mass, and high levels of cardiomyocyte apoptosis 7 days after the initiation of DOX treatment. In contrast, DOX-treated MHC-CB7 mice exhibited normal LV systolic function (pre-DOX FS = 63 ± 2%, post-DOX FS = 60 ± 2%, p>0.008), normal cardiac mass, and low levels of cardiomyocyte apoptosis. Western blot analyses indicated mTOR signaling was inhibited in DOX-treated NON-TXG mice, but not in DOX-treated MHC-CB7 mice. Accordingly, transgenic mice with cardiomyocyte-restricted constitutively active mTOR expression (MHC-mTORca) were studied. LV systolic function (pre-DOX FS = 64 +/- 2%, post-DOX FS 60 +/- 3%, p>0.008) and cardiac mass were normal in DOX-treated MHC-mTORca mice, despite similar levels of cardiomyocyte apoptosis as seen in DOX-treated NON-TXG mice.
Conclusions
These data suggest that DOX treatment induces acute cardiac dysfunction and reduces cardiac mass via p53-dependent inhibition of mTOR signaling, and that loss of myocardial mass, and not cardiomyocyte apoptosis, is the major contributor to acute DOX cardiotoxicity.
doi:10.1161/CIRCULATIONAHA.108.799700
PMCID: PMC2630181  PMID: 19103993
heart failure; apoptosis; myocytes
15.  Effect of nano-zinc oxide on doxorubicin- induced oxidative stress and sperm disorders in adult male Wistar rats 
Background: Doxorubicin (DOX), an anthracycline antibiotic, is a widely used anticancer agent. In spite of its high antitumor efficacy, the use of DOX in clinical chemotherapy is limited due to diverse toxicities, including gonadotoxicity.
Objective: We investigated the protective effect of nano-zinc oxide (nZnO) as an established antioxidant on DOX-induced testicular disorders.
Materials and Methods: In this experimental study 24 adult male Wistar rats were divided into four groups including one control and three experimentals (6 rats per group). They received saline (as control), DOX alone (6 mg/kg body weight, i.p.), nZnO alone (5 mg/kg body weight, i.p.), and nZnO followed by DOX. Animals were sacrificed 28 days after treatment and evaluations were made by sperm count and measuring sex hormone levels in plasma. Also total antioxidant power (TAP) and lipid peroxidation (LPO) in plasma were tested. Data was analyzed with SPSS-14 and one way ANOVA test. P<0.05 were considered to be statistically significant.
Results: In the DOX-exposed rats significant differences were found compared with the control group (p=0.001) in plasma total antioxidant power (TAP) (425.50±32.33 vs. 493.33±18.54 mmol/mL), Lipid peroxidation (LPO) (3.70±0.44 vs. 2.78±0.68 μmol/mL), plasma testosterone (3.38±0.69 vs. 5.40±0.89 ng/dl), LH (0.26±0.05 vs. 0.49±0.18 mlU/mL), sperm count (157.98±6.29 vs. 171.71±4.42×106/mL) and DNA damage (11.51±3.45 vs. 6.04±2.83%). Co-administration of nZnO significantly improved DOX-induced changes (p=0.013) in plasma TAP (471.83±14.51 mmol/mL), LPO (2.83±0.75 μmol/mL), plasma testosterone (5.00±1.07 ng/dl), LH (0.52±0.08 mlU/mL), sperm count (169.13±5.01×106/mL) and DNA damage (7.00±1.67%).
Conclusion: At the dose designed in the present investigation cytoprotective role of nano-zinc oxide through its antioxidant potential is illuminated in DOX-induced male gonadotoxicity.
PMCID: PMC3941413  PMID: 24639766
Doxorubicin; Antioxidant; DNA damage; Lipid peroxidation; Spermatogenesis; Testosterone
16.  Cardioprotective effect of Vedic Guard against doxorubicin-induced cardiotoxicity in rats: A biochemical, electrocardiographic, and histopathological study 
Pharmacognosy Magazine  2013;9(34):176-181.
Background:
Vedic Guard is a polyherbal formulation used in the treatment of various ailments, however, is not scientifically assessed for its effect on doxorubicin-induced cardiotoxicity.
Objective:
To find out the preventive role of Vedic Guard against doxorubicin-induced myocardial toxicity in rats.
Materials and Methods:
Cardiotoxicity was produced by doxorubicin (15 mg/kg for 2 weeks). Vedic Guard (270 mg/kg, orally) was administered as pre-treatment for 2 weeks and then for 2 weeks alternated with doxorubicin (DXR). The general observations, mortality, histopathology, biomarker like lactate dehydrogenase (LDH), creatine phosphokinase (CPK), aspartate aminotransferase (AST), alanine transaminase (ALT), electrocardiographic (ECG) parameters, antioxidants such as glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) were monitored after 3 weeks of last dose.
Results:
The repeated administration of DXR causes cardiomyopathy associated with an antioxidant deficit. Pre-treatment with Vedic Guard decreases serum enzyme viz LDH, CPK, AST, and ALT levels to that of normal values. Vedic Guard significantly protected the myocardium from the toxic effect of DXR, by increasing the levels of antioxidants such as GSH, SOD, and CAT and decreased the elevated level of malondialdehyde. The study shows significant alteration of ECG pattern in DXR administered rats. The characteristic findings were elevation of ST segment, reduction in P waves, QRS complex, and R-R interval. Vedic Guard showed a protective effect against DXR-induced altered ECG pattern. It also reduced the severity of cellular damage of the myocardium confirmed by histopathology.
Conclusion:
The results of the present study indicated cardioprotective effect of Vedic Guard might be attributed to its antioxidant activity.
doi:10.4103/0973-1296.111287
PMCID: PMC3680859  PMID: 23772115
Antioxidant; cardioprotective; cardiotoxicity; doxorubicin; vedic guard
17.  Effect of Telmisartan in Experimentally Induced Diabetetes Mellitus in Rats 
Background:
Increased oxidative stress is involved in the pathogenesis of diabetic nephropathy and neuropathy. Angiotensin II is a know factor in the pathogenesis of diabetic complications. The protective effects of ACEIs is known in diabetic nephropathy. Thus, Angiotensin receptor antagonists may have the same role. In this study, possible antidiabetic effect of Telmisartan and its tissues antioxidant effect in (STZ) induced diabetic rats, were studied
Methods :
The present study was done on 40 rats. They were divided into 2 main groups. Group I: 10 rats as control group, received distilled water. Group II: 30 rats subdivided into 3 equal subgroups as follow: Subgroup IIA: control diabetic group, received 55 mg/kg STZ intraperitoneally. Sub group IIB: diabetic rats, received 10 mg/kg telmisartan daily intragastrically. Sub group IIC: diabetic rats received 10mg/kg gliclazide daily intragastrically. Diabetes was induced by intraperitoneal injection of 55 mg/kg STZ for 8 weeks evidenced by significant increase in serum glucose, HBA1c and decreased Hb levels.
Results :
Diabetic rats showed a significant increase in tissue TBARs and a significant decrease in tissue (GSH) and (SOD) enzymes. Telmisartan or Gliclazide in diabetic rats produced a beneficial effect on serum glucose, Hb, HBA1c and restored tissue GSH and SOD with a fall in tissues TBARS.
Conclusion :
Telmisartan might be proved useful in the treatment of diabetes and its complications, as Gliclazide is restricted by its secondary failure rate and side effects.
PMCID: PMC3068643  PMID: 21475436
18.  Combined effects of p-coumaric acid and naringenin against doxorubicin-induced cardiotoxicity in rats 
Pharmacognosy Research  2011;3(3):214-219.
Background:
Doxorubicin (DOX) is the most active cytotoxic agents having efficacy in malignancies either alone or combined with other cytocidal agents. The clinical usefulness of the anthracycline drug has been precluded by cardiac toxicity. Many therapeutic interventions have been attempted to improve the therapeutic benefits of the drug. This study is based on the possible protective effects of combination of p-coumaric acid (PC) and naringenin (NR) on DOX induced cardiac toxicity in male Swiss albino rats.
Methods:
Total nine groups of Swiss albino rats were used, Group I (vehicle control) receive saline solution daily and Group II (disease control) receive saline solution daily up to 29th day and at 30th day a single dose of DOX (15 mg/kg i.p.) is given. PC alone (100 mg/kg/day p.o.) and (200 mg/kg/day p.o.) also NR alone (15 mg/kg/day) orally administer for 30 days. Similarly a standard drug Vit. E (100 mg/kg/day) administers alone for 30 days. Group PC/DOX and PC and NR/DOX receive PC (200 mg/kg/day) and combine PC (200 mg/kg/day).
Results:
Doxorubicin induced marked biochemical alterations characteristic of cardiac toxicity including increase in MDA level and decrease SOD, CAT & GSH level but prior administration of combination of PC & NR ahead of doxorubicin challenge ameliorated all these biochemical markers.
Conclusion:
The study proves the beneficial effects of combination of PC and NR in protecting animal against DOX induced cardiotoxicity.
doi:10.4103/0974-8490.85012
PMCID: PMC3193624  PMID: 22022172
Antioxidents; cardiotoxicity; doxorubicine; naringenin; p-coumaric acid
19.  Cardioprotective Effects of 20(S)-Ginsenoside Rh2 against Doxorubicin-Induced Cardiotoxicity In Vitro and In Vivo 
Doxorubicin (DOX) is considered as one of the best antineoplastic agents. However, its clinical use is restricted by its associated cardiotoxicity, which is mediated by the production of reactive oxygen species. In this study, 20(S)-ginsenoside Rh2 (Rh2) was explored whether it had protective effects against DOX-induced cardiotoxicity. In vitro study on H9C2 cell line, as well as in vivo investigation in one mouse and one rat model of DOX-induced cardiomyopathy, was carried out. The results showed that pretreatment with Rh2 significantly increased the viability of DOX-injured H9C2 cells. In the mouse model, Rh2 could suppress the DOX-induced release of the cardiac enzymes into serum and improved the occurred pathological changes through ameliorating the decreased antioxidant biomolecules and the cumulated lipid peroxidation malondialdehyde in heart tissues. In the rat model, Rh2 could attenuate the change of ECG resulting from DOX administration. Furthermore, Rh2 enhanced the antitumor activity of DOX in A549 cells. Our findings thus demonstrated that Rh2 pretreatment could effectively alleviate heart injury induced by DOX, and Rh2 might act as a novel protective agent in the clinical usefulness of DOX.
doi:10.1155/2012/506214
PMCID: PMC3483725  PMID: 23125868
20.  Antioxidant, Lipid Lowering, and Membrane Stabilization Effect of Sesamol against Doxorubicin-Induced Cardiomyopathy in Experimental Rats 
BioMed Research International  2013;2013:934239.
The present study was designed to evaluate the cardioprotective effect of sesamol against doxorubicin-induced cardiomyopathy in rats. In this study, the cardioprotective effect of sesamol against doxorubicin induced cardiomyopathy in experimental rats was evaluated at the dosage of 50 mg/kg bw. Doxorubicin was administered to rats at a total cumulative dose of 15 mg/kg through intraperitoneal route for 2 weeks in six-divided dose on 8th, 10th, 14th, 16th, 18th, and 21st day. After the last dose administration, the endogenous antioxidants and lipid peroxidation were estimated in heart tissue homogenate. Cardiac biomarkers such as troponin T, LDH, CK, and AST and lipid profiles such as cholesterol, triglycerides, HDL, LDL, and VLDL were estimated in serum. Sesamol has cardioprotective activity through normalization of doxorubicin-induced-altered biochemical parameters. Biochemical study was further supported by histopathological study, which shows that sesamol offered myocardial protection from necrotic damage. From these findings, it has been concluded that the sesamol has significant cardioprotection against doxorubicin induced cardiomyopathy via amelioration of oxidative stress, lipid lowering, and membrane stabilization effect.
doi:10.1155/2013/934239
PMCID: PMC3818820  PMID: 24228260
21.  Cardioprotective effect of ascorbic acid on doxorubicin-induced myocardial toxicity in rats 
Indian Journal of Pharmacology  2011;43(5):507-511.
Objective:
To investigate the preventive and curative role of ascorbic acid on doxorubicin (dox)-induced myocardial toxicity in rats.
Materials and Methods:
Animals were divided into five groups of six animals each. Group I served as normal control and received saline 5 ml/kg/day intraperitoneal (i.p.) for a period of 15 days. Group II animals received ascorbic acid 20 mg/kg per oral (p.o.) for 15 days as a pretreatment control (PR). Group III animals received dox 2.5 mg/kg body weight (b.w.), i.p., in six equal injections for two weeks for a total cumulative dose of 15 mg/kg b.w. Group IV animals received ascorbic acid 20 mg/kg p.o. for 15 days as a pretreatment followed by dox 2.5 mg/kg b.w., i.p., in six equal injections for two weeks for a total cumulative dose of 15 mg/kg body weight. Group V animals received dox 2.5 mg/kg b.w., i.p., in six equal injections for two weeks for a total cumulative dose of 15 mg/kg b.w. followed by ascorbic acid 20 mg/kg p.o for 15 days as post-treatment control (CR). The biochemical parameters such as tissue glutathione (GSH), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD), and enzyme biomarkers such as creatine phosphokinase (CPK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were monitored.
Results:
Pretreatment with ascorbic acid (20 mg/kg p.o.) significantly protected the myocardium from the toxic effect of dox (PR), by increasing the levels of antioxidant enzymes such as GSH, SOD, and CAT toward normal and decreased the levels of MDA, CPK, LDH, AST, and ALT as compared with dox-treated rats. Post-treatment with ascorbic acid to dox-treated group (CR) significantly increased the levels of tissue GSH, SOD, CAT and significantly decreased the level of MDA as compared with dox-treated group. It also reduced the severity of cellular damage of the myocardium as confirmed by histopathology. The restoration of the endogenous antioxidant system clearly depicts that ascorbic acid produced its protective effect by scavenging the reactive oxygen species.
Conclusion:
The results obtained in this study provide evidence for the usefulness of the ascorbic acid as a cardioprotective agent.
doi:10.4103/0253-7613.84952
PMCID: PMC3195117  PMID: 22021990
Ascorbic acid; cardiotoxicity; doxorubicin; free radicals
22.  Early Detection of Doxorubicin Cardiomyopathy Using 2-Dimensional Strain Echocardiography 
Ultrasound in medicine & biology  2007;34(2):208-214.
Doxorubicin is one of the most effective chemotherapeutic agents; however, it causes dose-dependent cardiomyopathy that may lead to heart failure. Conventional measures of ventricular function, such as fractional shortening, are insensitive in detecting early doxorubicin cardiomyopathy. We tested whether novel 2-dimensional radial strain echocardiography (2DSE) can detect early doxorubicin injury following chronic administration in a rat model. 14 male Sprague Dawley rats (240−260 g) received doxorubicin 2.5 mg/k IV per week for 10 (n=4) or 12 weeks (n=10); 17 controls received saline (10 weeks, n=7 and 12 weeks, n=10). Serial 2DSE from 0−12 weeks was done at the mid left ventricle using Vivid 7 echo (General Electric, Waukesha, WI, USA). With Q analysis software, radial strain was obtained. From the 2D image, anatomical M-mode through the anterior/inferior walls was used to measure fractional shortening. Fibrosis (Masson's trichrome) and caspase-3 activity were measured from excised hearts. Radial strain was lower in the doxorubicin group (12 week: 26.7±3 vs. 38.3±2.6%, p=0.006), with significant difference by 8 weeks whereas fractional shortening was lower with doxorubicin only after 12 weeks (30.2±1.7 vs. 37.6±1.4%, p=0.02). Doxorubicin group had lower cardiac mass (0.85±0.09 vs. 1.14±0.04 g, p=0.001), higher caspase-3 activity (1.95±0.2 fold increase over control, p<0.0001) and fibrosis (3.9±0.7 vs. 0.7±0.1%, p=0.005). Radial strain was related directly to cardiac mass (R=0.61, p=0.0007) and inversely to caspase-3 activity (R=−0.5, p=0.005). 2-dimensional radial strain echocardiography is useful in the early detection of doxorubicin cardiac injury and the reduction in radial strain is associated with histologic markers of doxorubicin cardiomyopathy.
doi:10.1016/j.ultrasmedbio.2007.07.018
PMCID: PMC2582214  PMID: 17935867
echocardiography; cardiomyopathy; heart failure; ventricular function; apoptosis
23.  Doxorubicin In Vivo Rapidly Alters Expression and Translation of Myocardial Electron Transport Chain Genes, Leads to ATP Loss and Caspase 3 Activation 
PLoS ONE  2010;5(9):e12733.
Background
Doxorubicin is one of the most effective anti-cancer drugs but its use is limited by cumulative cardiotoxicity that restricts lifetime dose. Redox damage is one of the most accepted mechanisms of toxicity, but not fully substantiated. Moreover doxorubicin is not an efficient redox cycling compound due to its low redox potential. Here we used genomic and chemical systems approaches in vivo to investigate the mechanisms of doxorubicin cardiotoxicity, and specifically test the hypothesis of redox cycling mediated cardiotoxicity.
Methodology/Principal Findings
Mice were treated with an acute dose of either doxorubicin (DOX) (15 mg/kg) or 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) (25 mg/kg). DMNQ is a more efficient redox cycling agent than DOX but unlike DOX has limited ability to inhibit gene transcription and DNA replication. This allowed specific testing of the redox hypothesis for cardiotoxicity. An acute dose was used to avoid pathophysiological effects in the genomic analysis. However similar data were obtained with a chronic model, but are not specifically presented. All data are deposited in the Gene Expression Omnibus (GEO). Pathway and biochemical analysis of cardiac global gene transcription and mRNA translation data derived at time points from 5 min after an acute exposure in vivo showed a pronounced effect on electron transport chain activity. This led to loss of ATP, increased AMPK expression, mitochondrial genome amplification and activation of caspase 3. No data gathered with either compound indicated general redox damage, though site specific redox damage in mitochondria cannot be entirely discounted.
Conclusions/Significance
These data indicate the major mechanism of doxorubicin cardiotoxicity is via damage or inhibition of the electron transport chain and not general redox stress. There is a rapid response at transcriptional and translational level of many of the genes coding for proteins of the electron transport chain complexes. Still though ATP loss occurs with activation caspase 3 and these events probably account for the heart damage.
doi:10.1371/journal.pone.0012733
PMCID: PMC2939875  PMID: 20856801
24.  Doxorubicin Cardiotoxicity and Cardiac Function Improvement After Stem Cell Therapy Diagnosed by Strain Echocardiography 
Doxorubicin (Dox) is one of the most effective chemotherapeutic agents; however, it causes dose-dependent cardiotoxicity. Evaluation of left ventricular function relies on measurements based on M-mode echocardiography. A new technique based on quantification of myocardial motion and deformation, strain echocardiography, has been showed promising profile for early detection of cardiac dysfunction. Different therapy strategies, such as flavonoid plant extracts and stem cells, have been investigated to improve heart function in toxic cardiomyopathy. This work aimed to assess early cardiac function improvement after treatments with either flavonoid extract from Camellia sinensis or mesenchymal stem cells in Dox cardiotoxicity using strain echocardiography. Twenty Wistar rats were randomly assigned to four groups. They received water (control, Dox, Dox + stem cells) or 100 mg/kg C. sinensis extract (Dox + C. sinensis) via gavage, daily, for four weeks. Animals also received saline (control) or 5 mg/kg doxorubicin (Dox, Dox + C. sinensis, Dox + stem cells) via intraperitoneal injection, weekly, for four weeks. Stem cells were injected (3 × 106 cells) through tail vein prior the beginning of the experiment (Dox + stem cells). Animals were evaluated by hematological, electrocardiography, echocardiography, and histopathological examinations. Dox cardiotoxicity was only diagnosed with strain echocardiography, detecting a decrease in ventricular function. C. sinensis extract did not prevent ventricular dysfunction induced by Dox. However, strain echocardiography examination revealed that Dox cardiotoxicity was significantly suppressed in rats treated with stem cells. In conclusion, strain echocardiography was able to detect precocity signs of heart failure and stem cell therapy showed cardioprotection effect against Dox cardiotoxicity.
doi:10.4172/1948-5956.1000184
PMCID: PMC3586317  PMID: 23459697
Echocardiography; Cardiotoxicity; Stem cell therapy; Flavonoid
25.  Effect of angiotensin II type 1 receptor blocker on renal function, arterial blood pressure and parathyroid hormone related protein over expression in cadmium induced nephrotoxicity in adult male rats 
Objective: To study the possible effect of angiotensin II type 1 Receptor blocker (AT1 blocker) on renal function, arterial blood pressure and parathyroid hormone related protein over expression in cadmium induced nephrotoxicity in adult male rats. Forty five rats were divided randomly into a control (group I), group II, received cadmium chloride at a dose of 5 mg/kg/day, orally, for nine weeks, group III received telmisartan (TEL) treatment (1 mg/kg/day, orally) one week before cadmium administration and continued for ten weeks. Results: Telmisartan significantly reduced blood urea nitrogen (BUN) and serum creatinine levels which were increased significantly by cadmium. Telmisartan significantly suppressed lipid peroxidation, compensated deficits in the antioxidant defenses (super oxide dismutase (SOD) level and catalase activity), decreased the elevations of nitric oxide (NO) and cadmium ion concentrations in renal tissue observed in Cd-treated rats. Group III had a significant decrease of urinary levels of total protein, N-acetyl-β-d-glucosaminidase (NAG), alkaline phosphatase (ALP) and γ-glutamyl-transpeptidase (GGT) and urinary 8-isoprostanes than those of group II. Telmisartan decreased the systolic blood pressure significantly than those of group II. Histopathological examination revealed that cadmium-induced renal tissue damage was ameliorated by telmisartan treatment. Immunohistochemical analysis revealed that telmisartan significantly decreased the cadmium-induced overexpression of parathyroid hormone receptor 1 (PTHR1) in renal tissue. RT-PCR analysis showed that Cd increased renal expression of PTHrP; however telmisartan could decrease the expression of PTHrP in group III. Conclusion: Blocking AT1 receptors significantly decreases PTHrP over expression and ameliorates renal dysfunction in Cd induced nephrotoxicity. These data suggest that Ang II might contribute to pathophysiology and deleterious effects in cadmium nephrotoxicity.
PMCID: PMC3669739  PMID: 23750309
Cadmium; parathyroid hormone related protein; nephrotoxicity; telmisartan

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