Research progress on the protective effects of polyphenols against doxorubicin-induced cardiotoxicity
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Abstract:
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; ReviewKeywords:
Cardiotoxicity
Cancer Therapy
With the rapid increase of cancer survivors due to improved diagnosis and therapy in the past decades, cancer treatment-related cardiotoxicity is becoming an urgent concern for modern society. The anthracycline doxorubicin (DOX), one of the most effective chemotherapeutic agents to date, is known to cause cardiomyopathy through induction of cardiomyocyte apoptosis. We previously showed that the cyclin-dependent kinase (CDK) inhibitor p21 promotes resistance against DOX-induced apoptosis. In this study, we demonstrated that CDK2 activity and expression were significantly increased following DOX exposure in mouse heart and cultured neonatal rat cardiomyocytes (NRCMs). DOX-induced apoptosis, as measured by cleavage of caspase 3 and PARP, TUNEL staining, and MTT assay, was significantly suppressed by inhibition of CDK2 activity using small-molecule inhibitors, or CDK2-specific siRNA. Conversely, overexpression of CDK2 augmented DOX-induced apoptosis. DOX injection-induced CDK2 activation in mouse heart was correlated with upregulation of the BH3-only protein Bim. Mechanistically, CDK2 mediated DOX-induced expression of Bim, which was essential in triggering Bax/Bak-dependent mitochondrial outer membrane permeabilization. Pharmacological inhibition of CDK2 robustly repressed DOX-induced mitochondrial depolarization. These findings identify CDK2 as a key determinant of DOX-induced apoptosis in cardiomyocytes. Activation of CDK2 is necessary for DOX-induced Bim expression and mitochondrial damage. Also, pharmacological inhibition of CDK2 might be an effective cardioprotective strategy against anthracycline cardiotoxicity.
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Molecular Mechanisms of Doxorubicin-induced CardiotoxicityDoxorubicin is among the most widely used drugs for the treatment of both adult and child cancers.Doxorubicin is the major cause of chemotherapy-induced cardiotoxicity that is dose limiting for the treatment of cancer.Many studies have explored pathophysiology and mechanisms of doxorubicininduced cardiotoxicity.Cellular and animal experiments proposed that doxorubicin-induced cardiotoxicity mechanism is multifactorial.Oxidative stress has been considered as the primary cause of cardiotoxicity.Although there is no effective treatment for doxorubicin-induced cardiotoxicity currently but many investigations are underway to discover preventive treatments whereas no specific treatment has been approved.Studies have shown that reactive oxygen species and topoisomerase 2b are molecular targets for cardioprotection.Therapeutic imaging methods and cardio-biomarkers may be helpful in the improvement of rapid detection of cardiac damage.In this review, effects of doxorubicin on DNA damage, free radical generation, mitochondrial damage, cell death and other parameters have been studied.
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The use of doxorubicin (Adriamycin), a widely used antineoplastic drug effective against several types of cancer, is limited by its cardiac toxicity, particularly in patients with concurrent risk factors for heart disease, including metabolic syndrome (MetS).Ogonowski et al report that a single moderate dose of doxorubicin produced significant cardiac toxicity in a rat dietary fructose model of MetS compared to rats on a standard diet.1 Before the administration of doxorubicin, the fructose-fed rats had hypertension, significantly elevated plasma triglycerides, and increased indices of lipid peroxidation and oxidative stress, but lower P-glycoprotein, expression and superoxide dismutase activity in their hearts. The fructose-fed rats were not obese, nor did they have significant hyperglycemia or echocardiographic evidence of cardiac dysfunction. However 3 days after doxorubicin treatment, ejection fraction and fractional shortening were significantly decreased only in the MetS rats and cardiac lipid peroxidation was further increased.1 Although the definition of MetS varies, hypertension, dyslipidemia, and increased inflammation and oxidative stress observed in these fructose-fed rats are criteria common to all.2 The relevance of this study is augmented by the use of a moderate model of MetS and dose of doxorubicin reflective of many patients who develop cardiotoxicity despite being relatively healthy before initiating doxorubicin treatment. P-glycoprotein, also called multiple drug-resistant protein1 and ATP-binding cassette (ABC) transporter 1, is responsible for the active transport of endogenous and exogenous compounds, including doxorubicin, out of cells. P-glycoprotein measured by western blot was decreased by 30% in the hearts of the fructose-fed rat before challenge with doxorubicin and was not altered after its administration (Ogonowski et al). The effect of inflammation on the expression of P-glycoprotein or its gene, ABCB1 (multiple drug resistant protein1), depends on the cell type.3,4 It is suppressed in hepatocytes and vascular and intestinal endothelial cells forming barriers of the brain and gut, yet increased in renal tubules. In a mouse model of lipopolysaccharide inflammation, the excretion of doxorubicin was decreased in the bile, but increased in the urine.5 The cardiotoxicity of doxorubicin is attributed primarily to its main metabolite doxorubicinol, which is ineffective as an antineoplastic agent. As circulating doxorubicinol does not cross the vascular endothelial barrier, its accumulation and toxicity in cardiomyocytes depends on enzymatic formation from doxorubicin within the heart.6 The short-chain alcohol dehydrogenases 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and carbonyl reductase1 are the primary enzymes responsible for catalyzing the formation of doxorubicinol from doxorubicin.7 Although most often associated with the reduction of the inactive steroids cortisone and 11-dehydrocorticosterone to the endogenous glucocorticoids cortisol and corticosterone, 11βHSD1 is an important reductase of diverse carbonyl-bearing xenobiotics, including doxorubicin,7 for entry into phase 1 biotransformation.8 11βHSD1 is expressed in many cells including cardiomyocytes, in addition to hepatocytes and the endothelial cells of barrier tissues such as the gut and vessels.9 Expression of 11β-HSD1 is increased in a variety of inflammatory conditions from arthritis to dementia, including MetS.9 Inflammatory cytokines promote TNF-α induced 11βHSD1 transcription, thus increasing activation of endogenous glucocorticoids that activate glucocorticoid receptor, a nuclear transcription factor that modulates diverse anti-inflammatory responses, including the transcription of 11βHSD1.9 Tissue inflammation associated with MetS targets the heart, vessels, and fat in particular; accordingly, 11βHSD1 is significantly increased in the heart in patients and animals with MetS.10,11 The same Th1 cell-associated inflammatory cytokines that increase the expression of 11βHSD1 also suppress P-glycoprotein expression and action.12 Tissue levels of doxorubicin or doxorubicinol were not measured for the Ogonowski study; nor was 11βHSD1. Notwithstanding, the authors' premise that the decrease in P-glycoprotein in the heart allowed more doxorubicin to enter the heart, is likely to be correct. Similarly, 11βHSD1 is expressed in the heart and increases in MetS;10,11 thus, it is likely that the conversion of doxorubicin to doxorubicinol was greater in the rats with MetS rats, resulting in increased toxicity. The use of selective inhibitors of carbonyl reductase1 and 11βHSD1 with doxorubicin to improve its therapeutic index has been suggested.7 Although selective inhibitors of 11βHSD1 exist, targeting enzymes with such wide substrate and tissue distributions and essential functions has been problematic. Despite promising preclinical studies, results of multiple clinical trials of the efficacy of selective inhibitors of 11βHSD1 in the treatment of a variety of conditions associated with chronic inflammation, including MetS, have been equivocal.13 However, these trials were for the treatment of chronic conditions and focused on reducing the impact of inappropriate glucocorticoid-mediated pathology, perhaps without adequate consideration of the many other 11βHSD1 substrates.9 Acute use of a selective 11βHSD1 inhibitor concurrent with doxorubicin treatment would decrease doxorubicin inactivation in the liver, thereby reducing the total dose required for treatment,7 and decrease its conversion to doxorubicinol within the heart, thus the cardiotoxicity seen more often in patients with underlying inflammatory conditions such as MetS.
Cardiotoxicity
Dyslipidemia
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This paper presents a review of the latest researches on the mechanism of cardiomyocyte death of doxorubicin-induced cardiotoxicity and the control methods,focusing on the clinical characteristics,mechanism,clinical detection and the preventive measures.Adramycin is one of the most widely used and successful antitumor drugs.However,its cumulative and dose-dependent cardiac toxicity has been a major concern of cancer therapeutic practice for decades.Recently,many studies support the idea that cardiomyocyte death by apoptosis and necrosis is a primary mechanism of DOX-induced cardiomyopathy.It can be very helpful in protecting the heart by developing not only early-stage assessment of cardiotoxicity,which is sensitive and specific,but also highly effective DOX antagonists.
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Doxorubicin as a chemotherapeutic drug is widely used for the treatment of patients with cancer. However, clinical use of this drug is hampered by its cardiotoxicity, which is manifested as electrocardiographic abnormalities, arrhythmias, irreversible degenerative cardiomyopathy and congestive heart failure. The precise mechanisms underlying the cardiotoxicity of doxorubicin are not clear, but impairment of calcium homeostasis, generation of iron complexes, production of oxygen radicals, mitochondrial dysfunction and cell membrane damage have been suggested as potential etiologic factors. Compounds that can neutralize the toxic effect of doxorubicin on cardiac cells without reducing the drug's antitumor activity are needed. In recent years, numerous studies have shown that herbal medicines and bioactive phytochemicals can serve as effective add-on therapies to reduce the cardiotoxic effects of doxorubicin. This review describes different phytochemicals and herbal products that have been shown to counterbalance doxorubicin-induced cardiotoxicity.
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Cardiotoxicity
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Doxorubicin is useful anticancer drug because it's used in treatment of acute leukemia, Hodgkin's and non-Hodgkin's lymphomas, and many other malignant neoplasm. The mechanism of doxorubicin induce cardiotoxicity is multifactorial includes free radical stress, mitochondrial dysfunction and calcium overload these are the main causes of doxorubicin-induced cardiotoxicity. Doxorubicin therapy augments oxidative stress and disturbs cytosolic calcium homeostasis, increases intracellular calcium levels from the sarcoplasmic reticulum through activation of the ryanodine receptor and by blighting calcium clearance systems in cardiomyocytes. In this condition the researchers trying to develop cardio-protective strategy to decrease this cardio-toxic effect without decreasing its anticancer effect. Now day's oncologists and pharmacologist work to find out how to decrease the cardiovascular risk and prevent doxorubicin adverse cardiovascular effect. Therefore, the aim of this study was to illustrate the molecular mechanism and possible amelioration of doxorubicin induced-cardiotoxicity via conventional drugs and natural products.
Cardiotoxicity
Dexrazoxane
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Cardiotoxicity is a frequent undesirable phenomenon observed during oncological treatment that limits the therapeutic dose of antitumor drugs and thus may decrease the effectiveness of cancer eradication. Almost all antitumor drugs exhibit toxic properties towards cardiac muscle. One of the underlying causes of cardiotoxicity is the stimulation of oxidative stress by chemotherapy. This suggests that an appropriately designed diet or dietary supplements based on edible plants rich in antioxidants could decrease the toxicity of antitumor drugs and diminish the risk of cardiac failure. This comprehensive review compares the cardioprotective efficacy of edible plant extracts and foodborne phytochemicals whose beneficial activity was demonstrated in various models in vivo and in vitro. The studies selected for this review concentrated on a therapy frequently applied in cancer, anthracycline antibiotic—doxorubicin—as the oxidative stress- and cardiotoxicity-inducing agent.
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Dose-dependent cardiotoxicity is the leading adverse reaction seen in cancer patients treated with doxorubicin. Currently, dexrazoxane is the only approved drug that can partially protect against this toxicity in patients, however, its administration is restricted to those patients receiving a high cumulative dose of anthracyclines. Investigations into the mechanisms of cardiotoxicity and efforts to improve cardioprotective strategies have been hindered by the limited availability of a phenotypically relevant in vitro adult human cardiac model system. Here, we adapted a readily reproducible, functional 3D human multi-cell type cardiac system to emulate patient responses seen with doxorubicin and dexrazoxane. We show that administration of two NRF2 gene inducers namely the semi-synthetic triterpenoid Bardoxolone methyl, and the isothiocyanate sulfurophane, result in cardioprotection against doxorubicin toxicity comparable to dexrazoxane as evidenced by an increase in cell viability and a decrease in the production of reactive oxygen species. We further show a synergistic attenuation of cardiotoxicity when the NRF2 inducers and dexrazoxane are used in tandem. Taken together, our data indicate that the 3D spheroid is a suitable model to investigate drug induced cardiotoxicity and we reveal an essential role of the NRF2 pathway in cardioprotection providing a novel pharmacological mechanism and intervention route towards the alleviation of doxorubicin-induced toxicity.
Cardiotoxicity
Dexrazoxane
Cardioprotection
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