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1.
Life Sci ; 283: 119849, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34343539

RESUMO

AIMS: Cardiotoxicity of doxorubicin frequently complicates treatment outcome. Aberrantly activated calcium/calmodulin pathway can eventually trigger signaling cascades that mediate cardiotoxicity. Therefore, we tested the hypothesis that trifluoperazine, a strong calmodulin antagonist, may alleviate this morbidity. MATERIALS AND METHODS: Heart failure and cardiotoxicity were assessed via echocardiography, PCR, immunohistochemistry, histopathology, Masson's trichrome staining and transmission electron microscopy. Whereas liver and kidney structural and functional alterations were evaluated histopathologically and biochemically. KEY FINDINGS: Results revealed that combination treatment with trifluoperazine could overcome doxorubicin-induced heart failure with reduced ejection fraction. Moreover, heart weight/body weight ratio and histopathological examination showed that trifluoperazine mitigated doxorubicin-induced cardiac atrophy, inflammation and myofibril degeneration. Transmission electron microscopy further confirmed the marked restoration of the left ventricular ultrastructures by trifluoperazine pretreatment. In addition, Masson's trichrome staining revealed that trifluoperazine could significantly inhibit doxorubicin-induced left ventricular remodeling by fibrosis. Of note, doxorubicin induced the expression of myocardial nuclear NF-κB-p65 and caspase-3 which were markedly inhibited by trifluoperazine, suggesting that cardioprotection conferred by trifluoperazine involved, at least in part, suppression of NF-κB and apoptosis. Furthermore, biochemical and histopathological examinations showed that trifluoperazine improved doxorubicin-induced renal and hepatic impairments both functionally and structurally. SIGNIFICANCE: In conclusion, the present in vivo study is the first to provide evidences underscoring the protective effects of trifluoperazine that may pave the way for repurposing this calmodulin antagonist in ameliorating organ toxicity by doxorubicin.


Assuntos
Apoptose/efeitos dos fármacos , Cardiotoxicidade , Cardiotoxinas/efeitos adversos , Doxorrubicina/efeitos adversos , Miocárdio/metabolismo , Fator de Transcrição RelA/metabolismo , Trifluoperazina/farmacologia , Animais , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Cardiotoxinas/farmacologia , Caspase 3/metabolismo , Doxorrubicina/farmacologia , Masculino , Camundongos , Miocárdio/patologia
2.
Mol Cell Biochem ; 476(8): 3099-3109, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33835331

RESUMO

While anthracyclines (ACs) are a class of chemotherapeutic agents that have improved the prognosis of many women with breast cancer, it is one of the most cardiotoxic agents used to treat cancer. Despite their reported dose-dependent cardiotoxicity, AC-based chemotherapy has become the mainstay of breast cancer therapy due to its efficacy. Elucidating the mechanisms of anthracycline-mediated cardiotoxicity and associated therapeutic interventions continue to be the main focus in the field of cardio-oncology. Herein, we summarized the current literature surrounding the mechanisms of anthracycline-induced cardiotoxicity, including the role of topoisomerase II inhibition, generation of reactive oxygen species, and elevations in free radicals. Furthermore, this review highlights the molecular mechanisms of potential cardioprotective interventions in this setting. The benefits of pharmaceuticals, including dexrazoxane, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, statins, and antioxidants in this setting, are reviewed. Finally, the mechanisms of emerging preventative interventions within this patient population including nutraceuticals and aerobic exercise are explored.


Assuntos
Antraciclinas/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Cardiotônicos/uso terapêutico , Cardiotoxicidade/prevenção & controle , Animais , Neoplasias da Mama/patologia , Cardiotoxicidade/etiologia , Cardiotoxicidade/patologia , Cardiotoxinas/efeitos adversos , Feminino , Humanos , Prognóstico , Fatores de Risco
3.
Rev. urug. cardiol ; 36(1): e36107, abr. 2021. ilus, tab
Artigo em Espanhol | LILACS, BNUY, UY-BNMED | ID: biblio-1252372

RESUMO

Las nuevas terapias oncológicas han logrado aumentar la sobrevida del paciente con cáncer, observando, sin embargo, un incremento de la morbilidad y mortalidad vinculadas a sus efectos secundarios. El desarrollo de eventos cardiovasculares adversos impacta negativamente en el pronóstico durante el tratamiento del cáncer, pero también en los supervivientes al cáncer, donde las enfermedades cardiovasculares (ECV) y las segundas neoplasias son la principal causa de muerte1-5. La cardiotoxicidad inducida por el tratamiento del cáncer se define como el conjunto de ECV derivadas de los tratamientos oncológicos. Su manifestación es variada e incluye el desarrollo de disfunción ventricular, insuficiencia cardíaca (IC), isquemia miocárdica, hipertensión arterial y arritmias, entre otras. Puede ser consecuencia tanto del efecto directo del tratamiento sobre la estructura y función cardíacas, como del desarrollo acelerado de ECV6-9. Frecuentemente se utiliza el término cardiotoxicidad como sinónimo de disfunción ventricular por quimioterapia (DV-QT). Dado que la cardiotoxicidad abarca un espectro más amplio de afectación cardiovascular, creemos conveniente hablar de DV-QT para referirnos a la afectación de la función sistólica del ventrículo izquierdo. La DV-QT y el desarrollo de IC representan una de las complicaciones más temidas por su impacto pronóstico en la esfera cardiovascular y oncológica, dado que limitan el arsenal terapéutico para el tratamiento del cáncer5,10. Han sido creadas diversas sociedades de cardio-onco-hematología con el fin de generar recomendaciones de práctica clínica y formar profesionales capacitados para el manejo de las complicaciones cardiovasculares del tratamiento del cáncer11. La cardio-oncología es una disciplina en creciente y continuo desarrollo. Creemos que es fundamental realizar tareas de formación médica continua, así como también estimular el trabajo conjunto de diversas especialidades para brindar una mejor asistencia. Este texto es el resultado del trabajo de un equipo multidisciplinario que incluye cardiólogos, hematólogos y oncólogos, y pretende brindar información a los integrantes del equipo de salud involucrados en la asistencia de pacientes oncológicos. Debido a su extensión, hemos decidido fraccionar el contenido en tres partes para facilitar su publicación.


New oncological therapies have been successful in increasing cancer patient survival, but they have also led to an increase in morbidity and mortality linked to their side effects. During cancer treatment, the development of cardiovascular side effects has a negative impact in prognosis, but also in cancer survivors, in whom cardiovascular diseases and secondary malignancies are the main cause of death. Cancer related cardiotoxicity is defined as the development of cardiovascular diseases related to cancer treatment. Clinical presentation is broad involving ventricular dysfunction, heart failure, myocardial ischemia, arterial hypertension and arrhythmias among others. This may result from the direct cardiovascular effect of a cancer treatment or accelerated development of cardiovascular diseases. Frequently, in the literature cardiotoxicity and chemotherapy related ventricular dysfunction are used as synonyms. However, cardiotoxicity includes a broad spectrum of cardiovascular manifestations, thus in this text we refer to chemotherapy related ventricular dysfunction as the presence of left ventricular systolic impairment. Chemotherapy related ventricular dysfunction and heart failure are two of the most feared complications of cancer treatment due to its impact on cardiovascular and oncological prognosis, affecting treatment options. Numerous worldwide cardio-onco-hematology societies have emerged to generate clinical practice guidelines and improve the diagnosis and evaluation of cardiovascular cancer treatment side effects. Cardio-Oncology is a discipline in continuous growth and development. We strongly believe that continuum medical education and a multidisciplinary approach is necessary to provide a quality health care. This text is the result of a multidisciplinary work involving cardiologists, hematologists and oncologists. It is our goal to provide information to the health care team involved in the assistance of cancer patients. Due to its extension, it will be published in three parts.


O desenvolvimento de novas terapias oncológicas levou a um aumento na sobrevida dos pacientes, mas ao mesmo tempo traz consigo morbidades relacionadas aos tratamentos. O desenvolvimento de efeitos cardiovasculares adversos tem um impacto negativo no prognóstico dos pacientes em tratamento, bem como nos pacientes considerados curados, nos quais doença cardiovascular e malignidades secundárias são as principais causas de morte. Cardiotoxicidade relacionada ao câncer é definida como o desenvolvimento de doença cardiovascular secundária ao tratamento. A gama de apresentações clínicas é ampla, podendo se manifestar como disfunção ventricular, insuficiência cardíaca, isquemia miocárdica, hipertensão arterial, arritmias, entre outras. Isto pode ser resultante de desenvolvimento e progressão acelerados de doença cardiovascular ou por efeito direto das terapias. Frequentemente é dito na literatura que cardiotoxicidade e disfunção ventricular relacionada à quimioterapia são sinônimos. Entretanto, cardiotoxicidade engloba um amplo espectro de manifestações cardiovasculares. Neste texto, portanto, nos referimos à disfunção ventricular causada por quimioterápicos exclusivamente como a presença de disfunção sistólica ventricular esquerda. Disfunção ventricular relacionada à quimioterapia e insuficiência cardíaca são duas das mais temidas complicações do tratamento oncológico devido ao seu impacto no prognóstico cardiovascular e oncológico, podendo afetar ainda a escolha e manutenção das opções terapêuticas. Diversas sociedades cardio-onco-hematológicas surgiram ao redor do mundo com o objetivo de gerar diretriz clínicas práticas e melhorar o diagnóstico e tratamento das complicações cardiovasculares resultantes das terapias oncológicas. A cardio-oncologia é uma disciplina em contínuo crescimento e desenvolvimento. Nós acreditamos fortemente que educação médica continuada e uma abordagem multidisciplinar são necessárias para um cuidado médico de qualidade. Este texto é o resultado de um trabalho multidisciplinar envolvendo cardiologistas, hematologistas e oncologistas. Nosso objetivo é de oferecer informação à equipe de cuidados em saúde envolvido na assistência destes pacientes. Devido à sua extensão, este texto será publicado em três partes.


Assuntos
Humanos , Disfunção Ventricular/induzido quimicamente , Disfunção Ventricular/prevenção & controle , Disfunção Ventricular/diagnóstico por imagem , Cardiotoxinas/efeitos adversos , Cardiotoxinas/farmacologia , Antineoplásicos/efeitos adversos , Biomarcadores , Medição de Risco , Assistência ao Paciente/normas , Insuficiência Cardíaca/induzido quimicamente
4.
Pediatr Hematol Oncol ; 38(5): 497-503, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33715575

RESUMO

BACKGROUND: Anthracycline chemotherapy is used to treat a variety of cancers. However, late cardiac effects of anthracycline chemotherapy, such as subclinical left ventricular dilatation and/or dysfunction, have been observed in more than half of long-term survivors of childhood cancers. A major risk factor for anthracycline cardiotoxicity is intrauterine growth restriction (IUGR). We assessed the significance of IUGR as an important risk factor for late cardiotoxic effects of anthracycline therapy in asymptomatic long-term survivors of childhood cancers. MATERIALS AND METHODS: The study included 61 survivors of childhood cancers. Cardiac functions were prospectively studied using both conventional and non-conventional echocardiographic methods (two-dimensional speckle tracking echocardiography) after completion of the treatment. The patients were divided into two groups based on their birth weights: Group 1 (patients with IUGR) and Group 2 (patients with normal birth weight). RESULTS: Conventional echocardiography revealed a similar and normal range of left ventricle systolic and diastolic functions in both groups. However, global longitudinal and circumferential strain values demonstrated subclinical left ventricular systolic dysfunction in both groups as compared with normal reference strain values. Furthermore, Group 1 patients had significantly lower global longitudinal and circumferential strain and strain rate values than those in Group 2 patients. CONCLUSION: Asymptomatic long-term survivors of childhood cancers with a history of IUGR may have an increased risk of anthracycline cardiotoxicity due to the low content of mitochondrial DNA (mtDNA). IUGR is a risk factor for late anthracycline cardiotoxicity.


Assuntos
Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Cardiotoxicidade/etiologia , Retardo do Crescimento Fetal , Neoplasias/tratamento farmacológico , Adolescente , Adulto , Peso ao Nascer , Sobreviventes de Câncer , Cardiotoxinas/efeitos adversos , Criança , Estudos Transversais , Retardo do Crescimento Fetal/etiologia , Humanos , Estudos Prospectivos , Fatores de Risco , Adulto Jovem
5.
Curr Cardiol Rev ; 17(3): 319-327, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33059567

RESUMO

INTRODUCTION: Hydroxychloroquine has been used for rheumatological diseases for many decades and is considered a safe medication. With the COVID-19 outbreak, there has been an increase in reports associating cardiotoxicity with hydroxychloroquine. It is unclear if the cardiotoxic profile of hydroxychloroquine is previously underreported in the literature or is it a manifestation of COVID-19 and therapeutic interventions. This manuscript evaluates the incidence of cardiotoxicity associated with hydroxychloroquine prior to the onset of COVID-19. METHODS: PubMED, EMBASE, and Cochrane databases were searched for keywords derived from MeSH terms prior to April 9, 2020. Inclusion eligibility was based on appropriate reporting of cardiac conditions and study design. RESULTS: A total of 69 articles were identified (58 case reports, 11 case series). The majority (84%) of patients were female, with a median age of 49.2 (range 16-92) years. 15 of 185 patients with cardiotoxic events were in the setting of acute intentional overdose. In acute overdose, the median ingestion was 17,857 ± 14,873 mg. 2 of 15 patients died after acute intoxication. In patients with long-term hydroxychloroquine use (10.5 ± 8.9 years), new onset systolic heart failure occurred in 54 of 155 patients (35%) with median cumulative ingestion of 1,493,800 ± 995,517 mg. The majority of patients improved with the withdrawal of hydroxychloroquine and standard therapy. CONCLUSION: Millions of hydroxychloroquine doses are prescribed annually. Prior to the COVID-19 pandemic, cardiac complications attributed to hydroxychloroquine were uncommon. Further studies are needed to understand the impact of COVID-19 on the cardiovascular system to understand the presence or absence of potential medication interactions with hydroxychloroquine in this new pathophysiological state.


Assuntos
Cardiotoxinas/efeitos adversos , Cardiopatias , Hidroxicloroquina/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19 , Feminino , Cardiopatias/induzido quimicamente , Cardiopatias/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
6.
Oxid Med Cell Longev ; 2020: 8819771, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33274007

RESUMO

The toxicity of doxorubicin (DOX) limits its clinical application. Nevertheless, at present, there is no effective drug to prevent DOX-induced cardiac injury. miR-204 is a newly discovered miRNA with many protective effects on cardiovascular diseases. However, little research has been done on the effects of miR-204 on DOX-induced cardiac injury. Our study is aimed at investigating the effect of miR-204 on DOX-induced myocardial injury. An adenoassociated virus system was used to achieve cardiac-specific overexpression of miR-204. Two weeks later, the mice were intraperitoneally injected with DOX (15 mg/kg) to induce cardiac injury. H9c2 myocardial cells were used to validate the role of miR-204 in vitro. Our study showed that miR-204 expression was decreased in DOX-treated hearts. miR-204 overexpression improved cardiac function and alleviated cardiac inflammation, apoptosis, and autophagy induced by DOX. In addition, our results showed that miR-204 prevented DOX-induced injury in cardiomyocytes by directly decreasing HMGB1 expression. Moreover, the overexpression of HMGB1 could offset the protective effects of miR-204 against DOX-induced cardiac injury. In summary, our study showed that miR-204 protected against DOX-induced cardiac injury via the inhibition of HMGB1, and increasing miR-204 expression may be a new treatment option for patients with DOX-induced cardiac injury.


Assuntos
Apoptose/efeitos dos fármacos , Cardiotoxinas/efeitos adversos , Doxorrubicina/efeitos adversos , Proteína HMGB1/metabolismo , MicroRNAs/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Apoptose/genética , Cardiotoxinas/farmacologia , Doxorrubicina/farmacologia , Proteína HMGB1/genética , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Inflamação/prevenção & controle , Masculino , Camundongos , MicroRNAs/genética , Miócitos Cardíacos/patologia
7.
Curr Environ Health Rep ; 7(4): 353-361, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33242201

RESUMO

PURPOSE OF REVIEW: Electronic cigarettes (e-cigs) are a source of metals. Epidemiologic and experimental evidence support that metals are toxic to the cardiovascular system. Little is known, however, about the role that e-cig metals may play as toxicants for the possible cardiovascular effects of e-cig use. The goal of this narrative review is to summarize the evidence on e-cig use and metal exposure and on e-cig use and cardiovascular toxicity and discuss the research needs. RECENT FINDINGS: In vitro studies show cytotoxicity and increased oxidative stress in myocardial cells and vascular endothelial cells exposed to e-liquids and e-cig aerosols, with effects partially reversed with antioxidant treatment. There is some evidence that the heating coil plays a role in cell toxicity. Mice exposed to e-cigs for several weeks showed higher levels of oxidative stress, inflammation, platelet activation, and thrombogenesis. Cross-over clinical experiments show e-cig use alters nitric oxide-mediated flow-mediated dilation, endothelial progenitor cells, and arterial stiffness. Cross-sectional evidence from large nationally representative samples in the USA support that e-cig use is associated with self-reported myocardial infarction. Smaller studies found associations of e-cig use with higher oxidized low-density protein and heart variability compared to healthy controls. Numerous studies have measured elevated levels of toxic metals in e-cig aerosols including lead, nickel, chromium, and manganese. Arsenic has been measured in some e-liquids. Several of these metals are well known to be cardiotoxic. Numerous studies show that e-cigs are a source of cardiotoxic metals. Experimental studies (in vitro, in vivo, and clinical studies) show acute toxicity of e-cigs to the vascular system. Studies of long-term toxicity in animals and humans are missing. Longitudinal studies with repeated measures of metal exposure and subclinical cardiovascular outcomes (e.g., coronary artery calcification) could contribute to determine the long-term cardiovascular effects of e-cigs and the potential role of metals in those effects.


Assuntos
Cardiotoxinas/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Sistemas Eletrônicos de Liberação de Nicotina , Metais/efeitos adversos , Vaping/efeitos adversos , Animais , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Células Endoteliais/efeitos dos fármacos , Fatores de Risco de Doenças Cardíacas , Humanos , Inflamação , Estresse Oxidativo/efeitos dos fármacos , Vaping/patologia , Vaping/fisiopatologia
8.
Zhonghua Zhong Liu Za Zhi ; 42(10): 838-842, 2020 Oct 23.
Artigo em Chinês | MEDLINE | ID: mdl-33113624

RESUMO

Cardiovascular toxicity of cancer patients in antineoplastic therapy is gradually paid widespread attention. Although many high-risk factors of cardiovascular toxicity associated with chemotherapy, targeted therapy or immunotherapy have been identified, it is still difficult to establish accurate risk prediction model. Traditional risk prediction model cannot adequately explain the differences in cardiovascular toxicity susceptibility among patients, makes it difficult to accurately screen high-risk groups, early diagnose and prevent cardiovascular toxicity. Finding susceptible genes of cardiovascular toxicity associated with antineoplastic therapy and incorporating single-nucleotide polymorphisms into risk prediction model can significantly improve the identification of high-risk population of cardiovascular toxicity.


Assuntos
Antineoplásicos , Sistema Cardiovascular/efeitos dos fármacos , Neoplasias/genética , Antineoplásicos/efeitos adversos , Cardiotoxinas/efeitos adversos , Humanos , Modelos Teóricos , Neoplasias/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Medição de Risco
9.
Sci Rep ; 10(1): 14720, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895481

RESUMO

Doxorubicin is a chemotherapeutic agent known to cause cardiotoxicity that is thought to be associated with oxidative stress. The aim of the current study is to investigate the role of grape polyphenols' antioxidant property as cardioprotective against doxorubicin-induced cardiotoxicity. Adult Wistar rats weighing 200 ± 20 g were divided into 3 different groups: a doxorubicin group that received a single intraperitoneal administration of doxorubicin (8.0 mg/kg body weight), an experimental group that received doxorubicin and grape polyphenol concentrate (25 mg/kg) via intragastric route, and the third group was a negative control group that received water only. On day 8, blood samples and tissues were harvested for analyses. The results indicated that grape polyphenol concentrate was able to reduce the signs of cardiotoxicity of doxorubicin through the reduction of aspartate aminotransferase activation, increasing the plasma antioxidant levels and decreasing the level of free radicals. The results also showed that grape polyphenol concentrate was able to reverse doxorubicin-induced microscopic myocardial damage. The myocardial protective effect of grape polyphenol might likely be due to the increase in the level and activity of the antioxidant enzymes, superoxide dismutase, catalase, and glutathione peroxidase. In conclusion, grape polyphenol concentrate displayed cardioprotective effect and was able to reverse doxorubicin-induced-cardiomyopathy in experimental rats.


Assuntos
Cardiotoxicidade/tratamento farmacológico , Doxorrubicina/efeitos adversos , Extrato de Sementes de Uva/farmacologia , Coração/efeitos dos fármacos , Polifenóis/farmacologia , Substâncias Protetoras/farmacologia , Vitis/química , Animais , Antioxidantes/farmacologia , Cardiotoxicidade/metabolismo , Cardiotoxinas/efeitos adversos , Catalase/metabolismo , Glutationa Peroxidase/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
10.
Toxicol Appl Pharmacol ; 406: 115213, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32877659

RESUMO

The limited availability of human heart tissue and its complex cell composition are major limiting factors for the reliable testing of drug efficacy and toxicity. Recently, we developed functional human and pig heart slice biomimetic culture systems that preserve the viability and functionality of 300 µm heart slices for up to 6 days. Here, we tested the reliability of this culture system for testing the cardiotoxicity of anti-cancer drugs. We tested three anti-cancer drugs (doxorubicin, trastuzumab, and sunitinib) with known different mechanisms of cardiotoxicity at three concentrations and assessed the effect of these drugs on heart slice viability, structure, function and gene expression. Slices incubated with any of these drugs for 48 h showed diminished in viability as well as loss of cardiomyocyte structure and function. Mechanistically, RNA sequencing of doxorubicin-treated tissues demonstrated a significant downregulation of cardiac genes and upregulation of oxidative stress responses. Trastuzumab treatment downregulated cardiac muscle contraction-related genes consistent with its clinically known effect on cardiomyocytes. Interestingly, sunitinib treatment resulted in significant downregulation of angiogenesis-related genes, in line with its mechanism of action. Similar to hiPS-derived-cardiomyocytes, heart slices recapitulated the expected toxicity of doxorubicin and trastuzumab, however, slices were superior in detecting sunitinib cardiotoxicity and mechanism in the clinically relevant concentration range of 0.1-1 µM. These results indicate that heart slice culture models have the potential to become a reliable platform for testing and elucidating mechanisms of drug cardiotoxicity.


Assuntos
Cardiotoxicidade , Cardiotoxinas/efeitos adversos , Coração/efeitos dos fármacos , Modelos Biológicos , Técnicas de Cultura de Tecidos , Adulto , Idoso , Animais , Antineoplásicos/efeitos adversos , Apoptose/efeitos dos fármacos , Doxorrubicina/efeitos adversos , Feminino , Coração/fisiologia , Humanos , Células-Tronco Pluripotentes Induzidas , Masculino , Pessoa de Meia-Idade , Suínos , Trastuzumab/efeitos adversos
11.
Circ Res ; 126(8): 947-964, 2020 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-32091972

RESUMO

RATIONALE: Drug-induced proarrhythmia is so tightly associated with prolongation of the QT interval that QT prolongation is an accepted surrogate marker for arrhythmia. But QT interval is too sensitive a marker and not selective, resulting in many useful drugs eliminated in drug discovery. OBJECTIVE: To predict the impact of a drug from the drug chemistry on the cardiac rhythm. METHODS AND RESULTS: In a new linkage, we connected atomistic scale information to protein, cell, and tissue scales by predicting drug-binding affinities and rates from simulation of ion channel and drug structure interactions and then used these values to model drug effects on the hERG channel. Model components were integrated into predictive models at the cell and tissue scales to expose fundamental arrhythmia vulnerability mechanisms and complex interactions underlying emergent behaviors. Human clinical data were used for model framework validation and showed excellent agreement, demonstrating feasibility of a new approach for cardiotoxicity prediction. CONCLUSIONS: We present a multiscale model framework to predict electrotoxicity in the heart from the atom to the rhythm. Novel mechanistic insights emerged at all scales of the system, from the specific nature of proarrhythmic drug interaction with the hERG channel, to the fundamental cellular and tissue-level arrhythmia mechanisms. Applications of machine learning indicate necessary and sufficient parameters that predict arrhythmia vulnerability. We expect that the model framework may be expanded to make an impact in drug discovery, drug safety screening for a variety of compounds and targets, and in a variety of regulatory processes.


Assuntos
Antiarrítmicos/química , Arritmias Cardíacas/tratamento farmacológico , Cardiotoxinas/química , Simulação por Computador , Descoberta de Drogas/métodos , Canal de Potássio ERG1/química , Antiarrítmicos/metabolismo , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/metabolismo , Cardiotoxicidade/metabolismo , Cardiotoxicidade/prevenção & controle , Cardiotoxinas/efeitos adversos , Cardiotoxinas/metabolismo , Descoberta de Drogas/tendências , Canal de Potássio ERG1/metabolismo , Feminino , Humanos , Síndrome do QT Longo/tratamento farmacológico , Síndrome do QT Longo/metabolismo , Aprendizado de Máquina , Masculino , Moxifloxacina/química , Moxifloxacina/metabolismo , Moxifloxacina/uso terapêutico , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Fenetilaminas/química , Fenetilaminas/metabolismo , Fenetilaminas/uso terapêutico , Estrutura Secundária de Proteína , Sulfonamidas/química , Sulfonamidas/metabolismo , Sulfonamidas/uso terapêutico , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/metabolismo , Inibidores da Topoisomerase II/uso terapêutico
12.
Int J Mol Sci ; 21(3)2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32023816

RESUMO

Duchenne muscular dystrophy (DMD) is a genetic disease characterized by muscle wasting and chronic inflammation, leading to impaired satellite cells (SCs) function and exhaustion of their regenerative capacity. We previously showed that lack of PKCθ in mdx mice, a mouse model of DMD, reduces muscle wasting and inflammation, and improves muscle regeneration and performance at early stages of the disease. In this study, we show that muscle regeneration is boosted, and fibrosis reduced in mdxθ-/- mice, even at advanced stages of the disease. This phenotype was associated with a higher number of Pax7 positive cells in mdxθ-/- muscle compared with mdx muscle, during the progression of the disease. Moreover, the expression level of Pax7 and Notch1, the pivotal regulators of SCs self-renewal, were upregulated in SCs isolated from mdxθ-/- muscle compared with mdx derived SCs. Likewise, the expression of the Notch ligands Delta1 and Jagged1 was higher in mdxθ-/- muscle compared with mdx. The expression level of Delta1 and Jagged1 was also higher in PKCθ-/- muscle compared with WT muscle following acute injury. In addition, lack of PKCθ prolonged the survival and sustained the differentiation of transplanted myogenic progenitors. Overall, our results suggest that lack of PKCθ promotes muscle repair in dystrophic mice, supporting stem cells survival and maintenance through increased Delta-Notch signaling.


Assuntos
Cardiotoxinas/efeitos adversos , Músculo Esquelético/lesões , Distrofia Muscular de Duchenne/genética , Proteína Quinase C-theta/genética , Células-Tronco/citologia , Animais , Diferenciação Celular , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos mdx , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/terapia , Fator de Transcrição PAX7/metabolismo , Receptor Notch1/metabolismo , Regeneração , Transdução de Sinais , Transplante de Células-Tronco , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo
13.
J Oncol Pharm Pract ; 26(2): 434-444, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31594518

RESUMO

BACKGROUND: Doxorubicin is one of the most commonly prescribed and time-tested anticancer drugs. Although being considered as a first line drug in different types of cancers, the two main obstacles to doxorubicin therapy are drug-induced cardiotoxicity and drug resistance. METHOD: The study utilizes systemic reviews on publications of previous studies obtained from scholarly journal databases including PubMed, Medline, Ebsco Host, Google Scholar, and Cochrane. The study utilizes secondary information obtained from health organizations using filters and keywords to sustain information relevancy. The study utilizes information retrieved from studies captured in the peer-reviewed journals on "doxorubicin-induced cardiotoxicity" and "doxorubicin resistance." DISCUSSION AND RESULTS: The exact mechanisms of cardiotoxicity are not known; various hypotheses are studied. Doxorubicin can lead to free radical generation in various ways. The commonly proposed underlying mechanisms promoting doxorubicin resistance are the expression of multidrug resistance proteins as well as other causes. CONCLUSION: In this review, we have described the major obstacles to doxorubicin therapy, doxorubicin-induced cardiotoxicity as well as the mechanisms of cancer drug resistance and in following the treatment failures.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Cardiotoxinas/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Doxorrubicina/efeitos adversos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/uso terapêutico , Cardiotoxicidade , Cardiotoxinas/uso terapêutico , Doenças Cardiovasculares/diagnóstico , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/fisiologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Humanos , Neoplasias/diagnóstico
14.
J Biol Regul Homeost Agents ; 33(5): 1425-1436, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576730

RESUMO

Aconitine (ACO), the main active component in Aconitum carmichaelii Debeaux (family: Ranunculaceae), has high cardiotoxicity, however the mechanisms of this effect remain unclear. Paeoniflorin (PF), the main chemical ingredient in herbaceous peony, can protect the heart from damage through antioxidant, vasodilatory and other effects. In this study, we focused on the mechanism by which PF reduces ACO cardiotoxicity. We selected H9c2 cells as the experimental model. MTT assay, Western blot analysis and real-time PCR were used to measure cell proliferation, apoptosis, ion channels and oxidative stress. Cell proliferation was significantly increased, the Bcl-2/Bax ratio and p53 level were upregulated, and Caspase-3 was slightly reduced in the ACO+PF group compared with the ACO group. SCN5A mRNA expression was significantly increased in the ACO+PF group compared with the ACO group, while RyR2 and Cx43 mRNA expression was decreased. Compared with the ACO group, the ACO+PF group showed marked decreases in extracellular lactate dehydrogenase (LDH) and intracellular malondialdehyde (MDA), while there was no difference in intracellular superoxide dismutase (SOD). The above data demonstrate that the cardiotoxicity of ACO in H9c2 cells was significantly decreased by PF.


Assuntos
Aconitina/efeitos adversos , Cardiotoxinas/efeitos adversos , Glucosídeos/farmacologia , Monoterpenos/farmacologia , Mioblastos/efeitos dos fármacos , Animais , Apoptose , Linhagem Celular , Estresse Oxidativo , Ratos
15.
J Am Coll Cardiol ; 74(13): 1714-1727, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31558256

RESUMO

Immune checkpoint inhibitors (ICIs) have been an important therapeutic advance in the field of cancer medicine, resulting in a significant improvement in survival of patients with advanced malignancies. Recent reports provided greater insights into the incidence of cardiovascular adverse events (CVAEs) with ICI use. Myocarditis is the most common CVAE associated with ICI. Pericardial diseases, Takotsubo syndrome, arrhythmias, and vasculitis constitute other significant AEs. Physicians should be aware of these infrequent, but potentially fatal toxicities associated with ICIs as their therapeutic use becomes widespread with a myriad of approvals by the U.S. Food and Drug Administration. Management involves prompt administration of high-dose corticosteroids and discontinuation of ICIs in severe myocarditis. This review summarizes the most updated evidence on epidemiology, pathophysiological mechanisms, and management strategies of various CVAEs associated with ICIs. Highlights from recent guidelines published by National Comprehensive Cancer Network on ICI-related CV toxicities have also been incorporated.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Cardiologia , Cardiotoxinas/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/imunologia , Fatores Imunológicos/efeitos adversos , Cardiologia/tendências , Doenças Cardiovasculares/epidemiologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Estados Unidos/epidemiologia
16.
Eur Heart J ; 40(48): 3913-3920, 2019 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-31318428

RESUMO

AIMS: Develop a score to predict the risk of major adverse cardiovascular events (MACE) after early stage breast cancer (EBC) to facilitate personalized decision-making about potentially cardiotoxic treatments and interventions to reduce cardiovascular risk. METHODS AND RESULTS: Using administrative databases, we assembled a cohort of women diagnosed with EBC in Ontario between 2003 and 2014, with follow-up through 2015. Two-thirds of the cohort were used for risk score derivation; the remainder were reserved for its validation. The outcome was a composite of hospitalizations for acute myocardial infarction, unstable angina, transient ischaemic attack, stroke, peripheral vascular disease, heart failure (HF), or cardiovascular death. We developed the score by regressing MACE incidence against candidate predictors in the derivation sample using a Fine-Gray model. Discrimination was assessed in the validation sample using Wolber's c-index for prognostic models with competing risks, while calibration was assessed by comparing predicted and observed MACE incidence. The risk score was derived in 60 294 women and validated in 29 810 women. Age, hypertension, diabetes, ischaemic heart disease, atrial fibrillation, HF, cerebrovascular disease, peripheral vascular disease, chronic obstructive pulmonary disease, and chronic kidney disease were significantly associated with MACE incidence and incorporated into the score. Ten-year MACE incidence was >40-fold higher for patients in the highest score decile compared to the lowest. The c-index was 81.9% (95% confidence interval 80.9-82.9%) at 5 years and 79.8% (78.8-80.8%) at 10 years in the validation cohort, with good agreement between predicted and observed MACE incidence. CONCLUSION: Cardiovascular prognosis after EBC can be estimated using patients' pre-treatment characteristics.


Assuntos
Neoplasias da Mama/complicações , Neoplasias da Mama/patologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Idoso , Cardiotoxinas/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Estudos de Casos e Controles , Transtornos Cerebrovasculares/epidemiologia , Tomada de Decisão Clínica , Estudos de Coortes , Morte , Diabetes Mellitus/epidemiologia , Feminino , Hospitalização , Humanos , Incidência , Ataque Isquêmico Transitório/epidemiologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Ontário/epidemiologia , Doenças Vasculares Periféricas/epidemiologia , Prognóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Medição de Risco , Acidente Vascular Cerebral/epidemiologia
17.
Biosci Rep ; 39(6)2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138757

RESUMO

Cancer is the leading cause of deaths around the world, especially in low- and middle- income countries. Pirarubicin (THP) is an effective drug for treatment of cancer, however, there still exists cardiotoxic effects of THP. Rutin is a kind of antioxidative compound extracted from plants, and might be a protective compound for cardiomyocytes. Phosphatidylinositol 3-hydroxy kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is critical for cellular survival, proliferation and metabolism, and thus we speculated rutin might perform a protective role in cardiomyocytes via PI3K/AKT/mTOR signaling pathway. And in this experiment, we first established a cardiotoxicity model of THP in mice model and cell models, and then found that rutin treatment could increase the proliferation of cells at low concentration. Then we explored the possible mechanism of the protective effect of rutin using Western blotting, quantitative polymerase chain reaction (qPCR) and ELISA methods, and found that the activation of PI3K/AKT/mTOR/nuclear factor-κB (NF-κB) signaling pathway was increased, and expression of downstream molecules involved in antioxidative stress were also increased. We further noticed that concentration of angiogenesis promoting factors were also increased in medium of cultured cells. Thus, we speculated that rutin could increase the activation of PI3K/AKT/mTOR signaling pathway, further decrease the oxidative stress level via increasing the expression of antioxidative stress enzymes with the increasing concentration of angiogenesis promoting factors, resulting in the protective role in cardiomyocytes and cardiac function.


Assuntos
Cardiotoxicidade/tratamento farmacológico , Cardiotoxinas/efeitos adversos , Doxorrubicina/análogos & derivados , Miócitos Cardíacos/metabolismo , Rutina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Cardiotoxinas/farmacologia , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Masculino , Camundongos , Miócitos Cardíacos/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo
18.
Biomed Khim ; 65(1): 51-56, 2019 Jan.
Artigo em Russo | MEDLINE | ID: mdl-30816097

RESUMO

The use of the anticancer drug doxorubicin (Dox) is limited due to its cardiotoxic effect. Using the method of automatic solid-phase peptide synthesis, we obtained a synthetic agonist of galanin receptors GalR1-3 [RAla14, His15]-galanine (2-15) (G), exhibiting cardioprotective properties. It was purified by high performance liquid chromatography (HPLC). The homogeneity and structure of the peptide was confirmed by HPLC, 1H-NMR spectroscopy and mass spectroscopy. The purpose of this study was to study the effect of G on the metabolism and cardiac function of rats with chronic heart failure (CHF) caused by Dox. Experiments were performed using male Wistar rats weighing 280-300 g. The control group of animals (C) was intraperitoneally treated with saline for 8 weeks; the doxorubicin group (D) of rats was intraperitoneally treated with Doх; the group of Doх + peptide G (D+G) received intraperitoneally injections of Doх and subcutaneously injections of peptide G; the peptide G group (G) was subcutaneously treated with G. At the beginning and at the end of the study, the concentration of thiobarbituric acid reactive substances (TBARS) and the activity of creatine kinase-MB (CK-MB) were determined in blood plasma; the animals were weighed, and cardiac function was assessed using echocardiography. At the end of the experiments, the hearts were used for determination of metabolites and assessment of oxidative phosphorylation in mitochondria. After 8-week treatment, animals of group D were characterized by severe heart failure, the lack of weight gain and an increase in plasma TBARS concentration and CK-MB activity. These disorders were accompanied by a decrease in the content of myocardial high-energy phosphates, a reduction inmitochondrial respiratory parameters, accumulation of lactate and glucose in the heart, and disturbances in the metabolism of alanine and glutamic and aspartic acids. Coadministration of G and Dox prevented the increase in plasma CK-MB activity and significantly reduced the plasma TBARS concentration. At the end of the experiments animals of group D+G had higher myocardial energy state and the respiratory control index of mitochondria than animals of group D, there was a decrease in anaerobic glycolysis and no changes in the amino acid content compared to the control. The peptide G significantly improved the parameters of cardiac function and caused weight gain in animals of group D+G in comparison with these parameters in group D. The obtained results demonstrate the ability of a novel agonist of galanin receptors GalR1-3 to attenuate Dox-indiced cardiotoxicity.


Assuntos
Doxorrubicina/efeitos adversos , Insuficiência Cardíaca/tratamento farmacológico , Peptídeos/farmacologia , Receptores de Galanina/agonistas , Animais , Cardiotoxinas/efeitos adversos , Coração , Insuficiência Cardíaca/induzido quimicamente , Masculino , Miocárdio , Ratos , Ratos Wistar
19.
Sci Rep ; 9(1): 2514, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30792528

RESUMO

Doxorubicin (DOX) is a potent chemotherapeutic with distinct cardiotoxic properties. Understanding the underlying cardiotoxic mechanisms on a molecular level would enable the early detection of cardiotoxicity and implementation of prophylactic treatment. Our goal was to map the patterns of different radiopharmaceuticals as surrogate markers of specific metabolic pathways induced by chemotherapy. Therefore, cardiac distribution of 99mTc-sestamibi, 99mTc-Annexin V, 99mTc-glucaric acid and [18F]FDG and cardiac expression of Bcl-2, caspase-3 and -8, TUNEL, HIF-1α, and p53 were assessed in response to DOX exposure in mice. A total of 80 mice (64 treated, 16 controls) were evaluated. All radiopharmaceuticals showed significantly increased uptake compared to controls, with peak cardiac uptake after one (99mTc-Annexin V), two (99mTc-sestamibi), three ([18F]FDG), or four (99mTc-glucaric acid) cycles of DOX. Strong correlations (p < 0.01) were observed between 99mTc-Annexin V, caspase 3 and 8, and TUNEL, and between [18F]FDG and HIF-1α. This suggests that the cardiac DOX response starts with apoptosis at low exposure levels, as indicated by 99mTc-Annexin V and histological apoptosis markers. Late process membrane disintegration can possibly be detected by 99mTc-sestamibi and 99mTc-glucaric acid. [18F]FDG signifies an early adaptive response to DOX, which can be further exploited clinically in the near future.


Assuntos
Cardiotoxinas/farmacologia , Doxorrubicina/farmacologia , Coração/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Anexina A5/genética , Apoptose/efeitos dos fármacos , Cardiotoxinas/efeitos adversos , Caspase 3/genética , Modelos Animais de Doenças , Doxorrubicina/efeitos adversos , Fluordesoxiglucose F18/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Coração/fisiopatologia , Humanos , Camundongos , Neoplasias/complicações , Neoplasias/patologia , Compostos de Organotecnécio/efeitos adversos , Compostos de Organotecnécio/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Compostos Radiofarmacêuticos/farmacologia
20.
Methods Mol Biol ; 1891: 247-255, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30414138

RESUMO

Fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder of progressive extra-skeletal ossification, is the most disabling form of heterotopic ossification (HO) in humans. Most people with FOP carry an activating mutation in a BMP type I receptor gene, ACVR1 R206H, that promotes ectopic chondrogenesis and osteogenesis and in turn HO. Advances in elucidating the cellular and molecular events and mechanisms that lead to the ectopic bone formation are being made through the use of genetically engineered mouse models that recapitulate the human disease. We describe methods for inducing heterotopic ossification in a mouse model that conditionally expresses the Acvr1 R206H allele.


Assuntos
Miosite Ossificante/patologia , Ossificação Heterotópica/patologia , Receptores de Ativinas Tipo I/genética , Alelos , Animais , Biomarcadores , Cardiotoxinas/efeitos adversos , Modelos Animais de Doenças , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos , Mutação , Miosite Ossificante/diagnóstico por imagem , Miosite Ossificante/etiologia , Ossificação Heterotópica/diagnóstico por imagem , Ossificação Heterotópica/etiologia , Microtomografia por Raio-X
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