Erdosteine prevents doxorubicin-induced cardiotoxicity in rats.

The clinical use of doxorubicin (Dxr) is limited by its cardiotoxic effects which are mediated by oxygen radicals. The purpose of this study was to investigate in vivo protective effects of erdosteine, an antioxidant agent because of its secondary active metabolites in vivo, against the cardiotoxicity induced by Dxr in rats. Three groups of male Sprague-Dawley rats (60 days old) were used. Group 1 was untreated group used as control; the other groups were treated with Dxr (single i.p. dosage of 20 mg kg(-1) b.wt.) or Dxr plus erdosteine (10 mg kg(-1) day(-1), orally), respectively. Erdosteine or oral saline treatment was done starting 2 days before Dxr for 12 days. The analyses were done at the 10th day of Dxr treatment. The protein carbonyl content, the activities of myeloperoxidase, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatine kinase (CK) as well as heart rate and blood pressures were significantly increased in Dxr group in comparison with the other groups. However, pulse pressure was decreased in Dxr group. The body and heart weights were decreased in both Dxr administered groups in comparison with control group. Disorganization of myocardial histology, picnotic nuclei, edema, and increase in collagen content around vessels were seen in the slides of Dxr group, whereas normal myocardial microscopy was preserved in Dxr plus erdosteine group. Collectively, these in vivo hemodynamic, enzymatic and morphologic studies provide an evidence for a possible prevention of cardiac toxicity in Dxr-treated patients.     

Aged garlic extract protects against doxorubicin-induced cardiotoxicity in rats

Clinical uses of doxorubicin (DOX), a highly active anticancer agent, are limited by its severe cardiotoxic side effects associated with increased oxidative stress and apoptosis. In this study we investigated whether aged garlic has protective effects against doxorubicin-induced free radical production and cardiotoxicity in male rats. A single dose of doxorubicin (25 mg/kg) caused increased both serum cardiac enzymes LDH and CPK activities and a significant increase malonyldialdehyde (MDA) in plasma. However, pretreatment of rats with aged garlic extract (250 mg/kg) for 27 days before doxorubicin therapy, reduced the activity of both enzymes, and significantly decreased of MDA production in plasma.     

Protective effects of telmisartan against acute doxorubicin-induced cardiotoxicity in rats

The therapeutic usefulness of doxorubicin (DXR), an anthracycline antibiotic, is limited by its cardiotoxicity. The present study investigated the effects of telmisartan, an angiotensin II receptor (AT1) antagonist against doxorubicin-induced cardiotoxicity in rats using biochemical and histopathological approaches. Doxorubicin (20 mg/kg) was injected intraperitoneally (ip) as a single dose and telmisartan (10 mg/kg) was administered orally for 7 days. Rats treated with DXR showed cardiotoxicity as evidenced by elevation of serum lactate dehydrogenase (LDH) activity, tissue malondialdehyde (MDA) level, catalase activity and a decrease in the level of glutathione (GSH). Pre- and post-treatment with telmisartan elicited a significant decrease in the activities of LDH and catalase in comparison with DXR-treated group. Furthermore, pretreatment with telmisartan also decreased lipid peroxidation (MDA level) and increased the GSH content in comparison with DXR group. However, the difference in lipid peroxidation and GSH content were not statistically significant in post-treated group. Histopathological studies showed disruption of cardiac tisuues in DXR groups. Pre- and post-treatment with telmisartan reduced the damage of cardiac tissue in rats. These results suggest that telmisartan treatment provides a significant protective effect against acute-doxorubicin induced cardiotoxicity in rats.     

Hyperbaric oxygen therapy does not potentiate doxorubicin-induced cardiotoxicity in rats

The present study was designed to investigate the protective effect of rosuvastatin on methionine-induced hyperhomocysteinaemia and haematological changes in albino rats. Methionine (1 g/kg, orally) administration to pathogenic control rats (i.e. group II) for 30 days significantly (P < 0.01) increased the levels of homocysteine, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C) and triglycerides (TGs) and decreased the levels of high-density lipoprotein cholesterol (HDL-C) in serum. Haematological observations of the peripheral blood smears of pathogenic rats (i.e. group II) fed with methionine also showed crenation of red blood cells cell membrane and significant (P < 0.01) increase in total leucocyte count, differential leucocyte count and platelet counts with significant (P < 0.01) decrease in the mean haemoglobin levels as compared to vehicle control rats (group I). Administration of rosuvastatin (0.5 mg/kg/day, orally) to hyperhomocysteinaemic rats for 30 days significantly (P < 0.01) decreased the levels of homocysteine, TC, TGs, LDL-C, VLDL-C and increased the levels of HDL-C in serum. The present results provide clear evidence that oral treatment with rosuvastatin produces homocysteine and lipid lowering activity and also reversal of haematological changes induced by methionine in rats.     

多柔比星致心脏毒性的可能信号途径

多柔比星(Dox)为临床常用的广谱、高效抗肿瘤药物,用于恶性淋巴瘤、实体瘤等多种癌症的治疗。然而,心脏毒性严重限制其临床应用。Dox诱发心脏毒性的作用机制十分复杂,其具体机制至今尚不清楚。Dox可明显上调心脏组织中ROS及TNF-α水平,引起心肌细胞内钙负载及线粒体细胞色素C释放,活化钙信号、p38MAPK、PI3K/Akt等多条信号途径。充分理解这些信号途径在Dox介导心脏毒性过程中的作用对于防治Dox心脏毒性具有重要的指导意义。本文就近年来Dox致心脏毒性的可能信号途径作简要综述。     

Protective effects of caffeic acid phenethyl ester on doxorubicin-induced cardiotoxicity in rats

The prevention of doxorubicin (DXR)-induced cardiotoxicity may be helpful to improve future DXR therapy. The aim of this study was to investigate the cardio-protective effects of caffeic acid phenethyl ester (CAPE), an antioxidant agent, on DXR-induced cardiotoxicity. Rats were divided into three groups and treated with saline, DXR and DXR + CAPE. Rats were treated with CAPE (10 micromol x kg(-1) day(-1) i.p.) or saline starting 2 days before a single dose of DXR (20 mg x kg(-1) i.p.). Ten days later, haemodynamic measurements were performed and the hearts were excised for biochemical analyses and microscopic examination. The heart rate and mean blood pressure were higher and the pulse pressure was lower in the DXR group than in the other two groups. The administration of DXR alone resulted in higher myeloperoxidase activity, lipid peroxidation and protein carbonyl content than in the other groups. The activities of superoxide dismutase and catalase were higher in DXR and DXR + CAPE groups than in the saline group. Rats in the DXR + CAPE group had increased catalase activity in comparison with the DXR group and high glutathione peroxidase activity in comparison with the other two groups. There was severe disruption of mitochondrial fi ne structure in the electron microscopy of the DXR group. In contrast, myocardial microscopy appeared nearly normal in the DXR + CAPE group (as de fi ned at the electron microscopic level). In light of these in vivo haemodynamic, enzymatic and morphological results, we conclude that CAPE pretreatment significantly attenuated DXR-induced cardiac injury, possibly with its antioxidant effects.     

Effect of selective and non-selective cyclooxygenase inhibitors on doxorubicin-induced cardiotoxicity and nephrotoxicity in rats

Context: Doxorubicin (DX) is a highly effective chemotherapeutic agent used widely in the treatment of solid tumors; however, its optimal use was associated with cardiotoxicity and nephrotoxicity. The exact mechanism of DX-induced cardiotoxicity and nephrotoxicity is not fully explored. Induction of cyclooxygenase-2 (COX-2) activity in either cardiac or renal tissue by DX has been previously reported, indicating a possible role of COX-2 in DX-induced tissue injury. However, the nature of this role in either tissue injury is an issue of controversy.

Objective: This study was the first that simultaneously evaluated the effects of a selective COX-2 inhibitor, nimesulide, and a non-selective COX-inhibitor, indomethacin, on DX-induced cardiotoxicity and nephrotoxicity in male Wistar rats.

Materials and methods: Rats were allocated into four groups. Control group, DX group (received 15 mg/kg, ip), DX + nimesulide (10 mg/kg/day, po) group, and DX + indomethacin (2 mg/kg/day, po) group. Nimesulide and indomethacin were started at the same day of DX injection and continued for 5 days.

Results: The results of the present study showed that inhibition of COX-2 either by selective or non-selective COX-2 inhibitor ameliorated DX-induced cardiotoxicity but aggravated DX-induced nephrotoxicity in rats, as evidenced biochemically and histopathologically.

Discussion and conclusion: Our study indicates that production of COX-2 is organ specific; consequently, the differential effect of COX-inhibitors should be considered in DX-treated patients. However, a wide scale experiment is needed for further confirmation and testing other members of COX-inhibitors (e.g. celecoxib and diclofenac).     

High fat diet-fed obese rats are highly sensitive to doxorubicin-induced cardiotoxicity

Often, chemotherapy by doxorubicin (Adriamycin^®) is limited due to life threatening cardiotoxicity in patients during and posttherapy. Recently, we have shown that moderate diet restriction remarkably protects against doxorubicin-induced cardiotoxicity. This cardioprotection is accompanied by decreased cardiac oxidative stress and triglycerides and increased cardiac fatty-acid oxidation, ATP synthesis, and upregulated JAK/STAT3 pathway. In the current study, we investigated whether a physiological intervention by feeding 40% high fat diet (HFD), which induces obesity in male Sprague-Dawley rats (250-275 g), sensitizes to doxorubicin-induced cardiotoxicity. A LD₁₀ dose (8 mg doxorubicin/kg, ip) administered on day 43 of the HFD feeding regimen led to higher cardiotoxicity, cardiac dysfunction, lipid peroxidation, and 80% mortality in the obese (OB) rats in the absence of any significant renal or hepatic toxicity. Doxorubicin toxicokinetics studies revealed no change in accumulation of doxorubicin and doxorubicinol (toxic metabolite) in the normal diet-fed (ND) and OB hearts. Mechanistic studies revealed that OB rats are sensitized due to: (1) higher oxyradical stress leading to upregulation of uncoupling proteins 2 and 3, (2) downregulation of cardiac peroxisome proliferators activated receptor-α, (3) decreased plasma adiponectin levels, (4) decreased cardiac fatty-acid oxidation (666.9 ± 14.0 nmol/min/g heart in ND versus 400.2 ± 11.8 nmol/min/g heart in OB), (5) decreased mitochondrial AMP-α2 protein kinase, and (6) 86% drop in cardiac ATP levels accompanied by decreased ATP/ADP ratio after doxorubicin administration. Decreased cardiac erythropoietin and increased SOCS3 further downregulated the cardioprotective JAK/STAT3 pathway. In conclusion, HFD-induced obese rats are highly sensitized to doxorubicin-induced cardiotoxicity by substantially downregulating cardiac mitochondrial ATP generation, increasing oxidative stress and downregulating the JAK/STAT3 pathway.     

Mechanism of protection of moderately diet restricted rats against doxorubicin-induced acute cardiotoxicity

Clinical use of doxorubicin (Adriamycin), an antitumor agent, is limited by its oxyradical-mediated cardiotoxicity. We tested the hypothesis that moderate diet restriction protects against doxorubicin-induced cardiotoxicity by decreasing oxidative stress and inducing cardioprotective mechanisms. Male Sprague-Dawley rats (250-275 g) were maintained on diet restriction [35% less food than ad libitum]. Cardiotoxicity was estimated by measuring biomarkers of cardiotoxicity, cardiac function, lipid peroxidation, and histopathology. A LD(100) dose of doxorubicin (12 mg/kg, ip) administered on day 43 led to 100% mortality in ad libitum rats between 7 and 13 days due to higher cardiotoxicity and cardiac dysfunction, whereas all the diet restricted rats exhibited normal cardiac function and survived. Toxicokinetic analysis revealed equal accumulation of doxorubicin and doxorubicinol (toxic metabolite) in the ad libitum and diet restricted hearts. Mechanistic studies revealed that diet restricted rats were protected due to (1) lower oxyradical stress from increased cardiac antioxidants leading to downregulation of uncoupling proteins 2 and 3, (2) induction of cardiac peroxisome proliferators activated receptor-alpha and plasma adiponectin increased cardiac fatty acid oxidation (666.9+/-14.0 nmol/min/g heart in ad libitum versus 1035.6+/-32.3 nmol/min/g heart in diet restriction) and mitochondrial AMPalpha2 protein kinase. The changes led to 51% higher cardiac ATP levels (17.7+/-2.1 micromol/g heart in ad libitum versus 26.7+/-1.9 micromol/g heart in diet restriction), higher ATP/ADP ratio, and (3) increased cardiac erythropoietin and decreased suppressor of cytokine signaling 3, which upregulates cardioprotective JAK/STAT3 pathway. These findings collectively show that moderate diet restriction renders resiliency against doxorubicin cardiotoxicity by lowering oxidative stress, enhancing ATP synthesis, and inducing the JAK/STAT3 pathway.     

Cranberry (Vaccinium macrocarpon) protects against doxorubicin-induced cardiotoxicity in rats

Doxorubicin (DOX) is a widely used cancer chemotherapeutic agent. However, it generates free oxygen radicals that result in serious dose-limiting cardiotoxicity. Supplementations with berries were proven effective in reducing oxidative stress associated with several ailments. The aim of the current study was to investigate the potential protective effect of cranberry extract (CRAN) against DOX-induced cardiotoxicity in rats. CRAN was given orally to rats (100 mg/kg/day for 10 consecutive days) and DOX (15 mg/kg; i.p.) was administered on the seventh day. CRAN protected against DOX-induced increased mortality and ECG changes. It significantly inhibited DOX-provoked glutathione (GSH) depletion and accumulation of oxidized glutathione (GSSG), malondialdehyde (MDA), and protein carbonyls in cardiac tissues. The reductions of cardiac activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and glutathione reductase (GR) were significantly mitigated. Elevation of cardiac myeloperoxidase (MPO) activity in response to DOX treatment was significantly hampered. Pretreatment of CRAN significantly guarded against DOX-induced rise of serum lactate dehydrogenase (LDH), creatine phosphokinase (CK), creatine kinase-MB (CK-MB) as well as troponin I level. CRAN alleviated histopathological changes in rats’ hearts treated with DOX. In conclusion, CRAN protects against DOX-induced cardiotoxicity in rats. This can be attributed, at least in part, to CRAN’s antioxidant activity.     

Fullerenol C60(OH)24 prevents doxorubicin-induced acute cardiotoxicity in rats

Results obtained in vitro suggested that fullerenol's antiproliferative properties and protective effects against doxorubicin (DOX) cytotoxicity are mediated by antioxidative and hydroxyl radical scavenger activity. The aim of this study was to examine the influence of fullerenol on acute cardiotoxicity after the administration of a single high dose of DOX in vivo. The experiment was performed on male Wistar rats randomly divided into five groups, each containing eight individuals, that were treated as follows: I) 0.9% NaCl, II) 10 mg/kg DOX, III) 50 mg/kg fullerenol 30 min before 10 mg/kg DOX, IV) 100 mg/kg fullerenol 30 min before 10 mg/kg DOX, and V) 100 mg/kg fullerenol. A functional, biochemical, hematological, and pathomorphological examination of the heart as well as an evaluation of oxidative stress parameters was conducted on days 2 and 14 after DOX administration. The function of the heart was investigated by monitoring heart contractility after the adrenaline infusion. Fullerenol, applied alone, did not alter basal values of investigated animals. Both doses of fullerenol, used as a pretreatment, did not alter the basal parameters of the animals. The 100 mg/kg dose of fullerenol showed better protection. Considering the mechanisms of DOX toxicity, fullerenol likely exerts its protective role as a free radical sponge and/or by removing free iron through the formation of a fullerenol-iron complex. Our results suggest that fullerenol might be a potential cardioprotective agent in DOX-treated individuals.     

自噬在多柔比星所致心脏毒性中的作用研究进展

多柔比星是一种广谱高效的抗肿瘤药物,但其心脏毒性是限制其临床应用的主要原因之一。多柔比星致心脏毒性的机制尚不完全清楚,通常认为与活性氧增加、线粒体损伤和细胞凋亡等机制相关。细胞自噬是一类依赖于溶酶体的蛋白质降解途径。近年来大量研究证实,自噬在多柔比星所致心脏毒性中具有重要作用。本文主要回顾自噬在多柔比星所致心脏毒性中的作用。     

Protective effects of berberine against doxorubicin-induced cardiotoxicity in rats by inhibiting metabolism of doxorubicin

Abstract

1.?The clinical use of doxorubicin, an effective anticancer drug, is severely hampered by its cardiotoxicity. Berberine, a botanical alkaloid, has been reported to possess cardioprotective and antitumor effects. In this study, we investigated the cardioprotective effect of berberine on doxorubicin-induced cardiotoxicity and the effect of berberine on the metabolism of doxorubicin.

2.?Adult male Sprague-Dawley rats were administered doxorubicin in the presence or absence of berberine for 2 weeks. Administration of berberine effectively prevented doxorubicin-induced body weight reduction and mortality in rats.

3.?Berberine reduced the activity of myocardial enzymes, including aspartate aminotransferase (AST), creatine kinase (CK), CK isoenzyme (CK-MB) and lactate dehydrogenase (LDH). Echocardiographic examination further demonstrated that berberine effectively ameliorated cardiac dysfunction induced by doxorubicin.

4.?Berberine inhibited the metabolism of doxorubicin in the cytoplasm of rat heart and reduced the accumulation of doxorubicinol (a secondary alcohol metabolite of doxorubicin) in heart.

5.?These data showed that berberine alleviated the doxorubicin-induced cardiotoxicity in rats via inhibition of the metabolism of doxorubicin and reduced accumulation of doxorubicinol selectively in hearts.     

Hydroxytyrosol ameliorates oxidative stress and mitochondrial dysfunction in doxorubicin-induced cardiotoxicity in rats with breast cancer

Oxidative stress is involved in several processes including cancer, aging and cardiovascular disease, and has been shown to potentiate the therapeutic effect of drugs such as doxorubicin. Doxorubicin causes significant cardiotoxicity characterized by marked increases in oxidative stress and mitochondrial dysfunction. Herein, we investigate whether doxorubicin-associated chronic cardiac toxicity can be ameliorated with the antioxidant hydroxytyrosol in rats with breast cancer. Thirty-six rats bearing breast tumors induced chemically were divided into 4 groups: control, hydroxytyrosol (0.5 mg/kg, 5 days/week), doxorubicin (1 mg/kg/week), and doxorubicin plus hydroxytyrosol. Cardiac disturbances at the cellular and mitochondrial level, mitochondrial electron transport chain complexes I–IV and apoptosis-inducing factor, and oxidative stress markers have been analyzed. Hydroxytyrosol improved the cardiac disturbances enhanced by doxorubicin by significantly reducing the percentage of altered mitochondria and oxidative damage. These results suggest that hydroxytyrosol improve the mitochondrial electron transport chain. This study demonstrates that hydroxytyrosol protect rat heart damage provoked by doxorubicin decreasing oxidative damage and mitochondrial alterations.     

一氧化氮在阿霉素心脏毒性中的双重作用

蒽环类抗生素阿霉素（Doxombicin,DOX）是一种高效的抗肿瘤药物,主要用于治疗血液学疾病以及各种实体瘤。但因其引发多重生物化学通道的细胞损伤,进而导致严重的剂量依赖性心脏毒性作用,使其临床应用及治疗指数受到限制与影响。NO是与心脏病理生理学相关的重要生物信使分子,其在阿霉素心脏毒性中的重要作用受到了普遍的关注。本文通过查阅近年来的国内外有关文献,对于此焦点问题进行了分析总结。     

阿霉素心肌毒性机制研究进展

阿霉素属于蒽醌类抗肿瘤药,临床上用于白血病、淋巴瘤、乳腺癌等多种恶性肿瘤的治疗,且作用广谱,效果显著,但其所致心肌毒性不仅限制了其临床使用,也影响了患者的生活质量。因此,探讨阿霉素诱导心肌毒性的作用机制具有重要意义,本文就近年来阿霉素所致心肌毒性的作用机制研究做一综述。     

Resveratrol-induced autophagy promotes survival and attenuates doxorubicin-induced cardiotoxicity

Resveratrol (RSV) has many biological effects, including antitumor and antiviral activities, and vascular protection. Recent studies have suggested that RSV exerts its antitumor effects through induction of autophagy by an unknown mechanism. Doxorubicin (DOX) is a wide spectrum antitumor drug, but its clinical application is limited by its cardiotoxicity. This study evaluated whether the manipulation of autophagy could attenuate the cardiotoxic effects of DOX in vitro as well as in a rat model of DOX-induced cardiotoxicity. We found that DOX induced H9C2 cell apoptosis by inhibiting AMPK activation and promoting pro-apoptotic protein expression through p38MAPK/p53 signaling. RSV-treated H9C2 cells showed increased autophagy through the AMPK/mTOR/Ulk1 pathway. When DOX and RSV were combined, apoptosis was decreased, despite a slight increase in the autophagy ratio. The same result was observed in the rat model of DOX-induced cardiotoxicity. Injection with DOX or RSV alone, or in combination, for a week, resulted in a reduced apoptotic ratio in the combination group compared with the DOX alone group. Our results strongly indicate that this co-treatment strategy with RSV can attenuate the cardiotoxic effects of DOX. Our findings may have important clinical implications.     

Morphine is protective against doxorubicin-induced cardiotoxicity in rat

Doxorubicin (DOX) is an anthracycline antibiotic that is widely used as a chemotherapeutic agent. However, usefulness of this agent is limited due to its cardiotoxic effects. The aim of this study was to investigate the potential protective effects of morphine against DOX-induced cardiotoxicity in rats. Male Sprague-Dawley rats were treated with morphine (10mg/kg i.p.) and/or DOX (1.25mg/kg i.p.), 4 times per week, for 4 weeks. Mortality, general condition and body weight of the animals were observed during the whole treatment, and for a further 4-week period, until the end of experiment. Evaluation of cardioprotective efficacy of morphine was performed by analyzing the electrocardiographic parameters and contractility force of left ventricular papillary muscle. Necropsy was also performed at the end of the experiment, and heart excision, weight and macroscopic examination were done before histological evaluation. Doxorubicin caused heart disturbances manifested by prominent electrocardiographic changes (S(alpha)-T prolongation), decrease of the heart contractility, as well as histopathologically verified myocardial lesions. The changes in heart parameters were accompanied by 50% mortality rate, significant decline in body mass and severe effusion intensity score of the animals. Application of morphine before each dose of DOX either significantly reduced or completely prevented its toxic effects. Therefore, since morphine had very good protective effects against a high dose of DOX given as a multiple, low, unitary dose regimen, not only on the heart but on the whole rat as well, it could be recommended for further investigation in this potentially new indication for clinical application.     

Autophagy upregulation promotes survival and attenuates doxorubicin-induced cardiotoxicity

This study evaluated whether the manipulation of autophagy could attenuate the cardiotoxic effects of doxorubicin (DXR) in vitro as well as in a tumour-bearing mouse model of acute doxorubicin-induced cardiotoxicity. We examined the effect of an increase or inhibition of autophagy in combination with DXR on apoptosis, reactive oxygen species (ROS) production and mitochondrial function. H9C2 rat cardiac myoblasts were pre-treated with bafilomycin A1 (autophagy inhibitor, 10 nM) or rapamycin (autophagy inducer, 50 μM) followed by DXR treatment (3 μM). The augmentation of autophagy with rapamycin in the presence of DXR substantially ameliorated the detrimental effects induced by DXR. This combination treatment demonstrated improved cell viability, decreased apoptosis and ROS production and enhanced mitochondrial function. To corroborate these findings, GFP-LC3 mice were inoculated with a mouse breast cancer cell line (EO771). Following the appearance of tumours, animals were either treated with one injection of rapamycin (4 mg/kg) followed by two injections of DXR (10 mg/kg). Mice were then sacrificed and their hearts rapidly excised and utilized for biochemical and histological analyses. The combination treatment, rather than the combinants alone, conferred a cardioprotective effect. These hearts expressed down-regulation of the pro-apoptotic protein caspase-3 and cardiomyocyte cross-sectional area was preserved. These results strongly indicate that the co-treatment strategy with rapamycin can attenuate the cardiotoxic effects of DXR in a tumour-bearing mouse model.