PPARα Ameliorates Doxorubicin-Induced Cardiotoxicity by Reducing Mitochondria-Dependent Apoptosis via Regulating MEOX1
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Abstract:
Doxorubicin (DOX), which is widely used as chemotherapeutic drug in clinical work, can cause serious cardiotoxicity, and greatly reduce the survival rate, as well as quality of life of chemotherapy patients. Peroxisome proliferation activated receptor α (PPARα) is a kind of ligand activated receptor in the nuclear hormone receptor family that regulates multiple gene expression. Previous studies showed that PPARα possesses anti-apoptotic and cardio-protective effects. However, its role in DOX-induced cardiotoxicity is rarely reported. In this study, we were surprised to find decreased expression of PPARα in the heart of tumor-bearing mice treated by DOX, and there's no such phenomenon in tumor tissues. Next, we observed that PPARα agonist, fenofibrate (FENO), did not facilitates tumor progression, but enhanced cardiac function in tumor-bearing mice treated by DOX. Subsequently, recombinant adeno-associated virus serotype 9 (rAAV9) was used to manipulate the expression of PPARα in the heart of DOX-induced mice. Our results showed that PPARα gene delivery reduced cardiac dysfunction and mitochondria-dependent apoptosis in DOX-induced mice. Furthermore, we found that PPARα directly regulated the expression of mesenchyme homeobox 1 (MEOX1). Most importantly, cardioprotective effects of PPARα could be neutralized by knocking down MEOX1. In summary, PPARα plays a vital role in DOX-induced cardiotoxicity and is a promising treatment target.Keywords:
Cardiotoxicity
Doxorubicin is a major culprit in chemotherapy-induced cardiotoxicity, which is the chief limiting factor in delivering optimal chemotherapy to cancer patients. Although extensive efforts have been devoted, no chemical synthesized drugs or natural compounds are available to prevent the harmful action of doxorubicin without reducing its anti-cancer efficacy. Accumulative experimental evidence has shown that polyphenols can prevent doxorubicin-induced cardiotoxicity largely due to their anti-cancer and cardio protective properties. We elaborated on the potential mechanisms associated with doxorubicin-induced cardiotoxicity and reviewed published literatures about the protective effects of polyphenols on doxorubicin-induced cardiotoxicity to provide novel strategies for the study of cardioprotective drugs.
Key words:
Doxorubicin/AE; Cardiomyopathies/CI; Phenols/PD; Review
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This study was aimed to investigate the protective effect of lignanoid against doxorubicin-induced cardiotoxicity in rats. Doxorubicin were administered at the dosage of 5 mg/kg once a week, ip for a period of 5 consecutive weeks. Lignanoid were administered at the dosages of 25, 50 and 100mg/kg, po by gavage for 7 consecutive days in a week for 5 weeks. Lignanoid at the doses of 50 and 100 mg/kg significantly reduced CK-MB, NO and LDH and increased GST levels in the doxorubicin-treated group. Thus, lignanoid ameliorated doxorubicin-induced cardiotoxicity by reducing oxidative stress, abnormal cellular morphology in rat. This study indicates the protective effect of lignanoid against doxorubicin-induced cardiotoxicity.
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This study investigated the cardioprotective effect of repeated remote ischemic preconditioning (rRIC) on doxorubicin-induced cardiotoxicity in mice.Doxorubicin is an effective chemotherapeutic agent for a wide range of tumor types but its use and dosing are limited by acute and chronic cardiotoxicity. Remote ischemic conditioning (RIC) is cardioprotective in multiple cardiovascular injury models, but the effectiveness of rRIC in doxorubicin-induced cardiotoxicity has not been fully elucidated.rRIC was performed on mice before and after doxorubicin administration. Cardiac function was assessed by echocardiography and myocardial biology was tested by molecular approaches.Doxorubicin administration induced acute cardiotoxicity, as indicated by reduced cardiac function, reduced myocyte cross-section area and increased extracellular collagen deposition, increased circulating cardiac muscle damage markers, and decreased heart weight. Doxorubicin also adversely affected other organs, including the kidney, liver, and spleen, as evaluated by circulating markers or organ weight loss. rRIC not only abrogated doxorubicin-induced cardiotoxicity (left ventricular ejection fraction, doxorubicin 47.5 ± 1.1%, doxorubicin + rRIC 51.6 ± 0.7%, p = 0.017), but also was associated with multiorgan protection. Within the myocardium, rRIC attenuated doxorubicin-induced cardiomyocyte apoptosis, reduced inflammation, and increased autophagy signaling.rRIC may be a promising approach to reduce doxorubicin-induced cardiotoxicity.
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Ferroptosis, an iron-dependent form of regulated cell death, has received increasing attention for its pathophysiologic contribution to the onset and development of doxorubicin-induced cardiotoxicity. Moreover, modulation of ferroptosis with specific inhibitors may provide new therapeutic opportunities for doxorubicin-induced cardiotoxicity. Here, we will review the molecular mechanisms and therapeutic promise of targeting ferroptosis in doxorubicin-induced cardiotoxicity.
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Doxorubicin is a highly effective chemotherapeutic agent widely used to treat a variety of cancers. However, the clinical application of doxorubicin is limited due to its adverse effects on several tissues. One of the most serious side effects of doxorubicin is cardiotoxicity, which results in life-threatening heart damage, leading to reduced cancer treatment success and survival rate. Doxorubicin-induced cardiotoxicity results from cellular toxicity, including increased oxidative stress, apoptosis, and activated proteolytic systems. Exercise training has emerged as a non-pharmacological intervention to prevent cardiotoxicity during and after chemotherapy. Exercise training stimulates numerous physiological adaptations in the heart that promote cardioprotective effects against doxorubicin-induced cardiotoxicity. Understanding the mechanisms responsible for exercise-induced cardioprotection is important to develop therapeutic approaches for cancer patients and survivors. In this report, we review the cardiotoxic effects of doxorubicin and discuss the current understanding of exercise-induced cardioprotection in hearts from doxorubicin-treated animals.
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The study of mechanisms underlying cardiotoxicity of doxorubicin and the development of strategies to mitigate doxorubicin-induced cardiotoxicity are the most relevant issues of modern cardio-oncology. This is due to the high prevalence of cancer in the population and the need for frequent use of highly effective chemotherapeutic agents, in particular anthracyclines, for optimal management of cancer patients. However, while being a potent agent to counteract cancer, doxorubicin also affects the cardiovascular systems of patients undergoing chemotherapy in a significant and unfavorable fashion. Consecutively reviewed in this article are risk factors and mechanisms of doxorubicin cardiotoxicity, and the essential strategies to mitigate cardiotoxic effects of doxorubicin treatment in cancer patients are discussed.
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Doxorubicin is a potent anticancer agent effective in a wide range of malignancies, but its use is limited by dose-dependent late cardiotoxicity. Severe doxorubicin cardiotoxicity has been associated with a poor prognosis and a high mortality rate, and until recently has been thought to be irreversible. We describe the cases of three patients with well-documented severe left ventricular dysfunction due to doxorubicin who had complete clinical recovery with return of cardiac function to normal. Because severe doxorubicin cardiotoxicity is reversible in some patients, aggressive supportive therapy is warranted.
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Doxorubicin is a widely used chemotherapeutic agents and is now part of standard therapeutic regimens for a variety of cancers (eg, hematopoietic malignancies and advanced solid tumors of the breast, ovary, thyroid, and bone). However, a potentially lethal and dose-dependent cardiotoxicity that appears within a short time after treatment limits the usage of doxorubicin in cancer patients. Although the mechanism of doxorubicin-induced cardiotoxicity is not completely understood, it is thought that free radical-induced oxidative stress and excessive production of reactive oxygen species are primary drivers of its toxicity. In this study, we compared the doxorubicin-induced cardiotoxicity of ICR mice obtained from three different sources and evaluated the utility of Korl:ICR stock established by the Korean FDA. Because doxorubicin-induced cardiotoxicity is thought to involve the excessive generation of ROS followed by oxidative stress, we determined the representative tissue index of oxidation, lipid peroxidation, and antioxidant, glutathione (GSH), as well as the parameters of heart injury. Doxorubicin treatment successfully induced cardiotoxicity as evidenced by histological examination and serum parameters (eg, levels of LDH and CK activities) in ICR mice. It was accompanied by increased lipid peroxidation and a decrease in both cysteine and GSH, further supporting previous reports that oxidative stress is a potential mechanism of doxorubicin-induced cardiotoxicity. Of interest, we did not observe a significant difference in doxorubicin-induced cardiotoxicity among mice of different origins. Collectively, our results suggest that Korl:ICR strain may be useful in the research of doxorubicin-induced cardiotoxicity.
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Abstract: Background: Doxorubicin is an anthracycline anti-cancer drug and one of the most widely used chemotherapeutic medications to treat both solid and hematological tumors. However, due to the major adverse effect of cardiotoxicity, the clinical use of doxorubicin was highly restricted. Objectives: The current research was undertaken to explore the salutary properties of the triptonide on the doxorubicin-induced cardiotoxicity in rats. Materials and Methods: Rats were given 2.5 mg/kg of doxorubicin to produce cardiotoxicity, which was then treated with 25 mg/kg of triptonide. A set of rats was treated with 50 mg/kg of triptonide alone. Plethysmography on the tail-cuff was used to measure the blood pressure indicators. Using assay kits, the concentrations of oxidative and antioxidative biomarkers and cardiac function markers were measured. Using established techniques, the antioxidant enzyme activity was assessed. The histopathological study was performed on the heart tissues to analyze the doxorubicin-induced histological changes. Results: The heart weight was improved by triptonide treatment in the doxorubicin-induced rats. Triptonide effectively reduced the blood pressure indicators in the doxorubicin-induced rats. In the doxorubicin-induced rats, triptonide significantly decreased the LDH, CK, and AST activities and the status of myoglobin, H-FABP, GP-BB, and CK-MB. The triptonide therapy decreased the levels of INF-γ, MCP-1, and TGF-β in the serum of doxorubicin-induced rats. The findings of the histopathological examination showed that triptonide had therapeutic benefits. Conclusion: In summary, the results of this study supported the hypothesis that triptonide could ameliorate the biochemical and histological changes in the rats' hearts that were caused by doxorubicin. Keywords: Creatine kinase, Cardiac damage, Myoglobulin, Doxorubucin, Triptonide.
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