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1.
Curr Oncol ; 28(5): 4139-4156, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-34677269

RESUMO

While developments in cancer therapeutics have greatly reduced morbidity and mortality in females with breast cancer, it comes at a cost of an increased risk of cardiovascular complications. In particular, anthracyclines, like doxorubicin, which are a mainstay of current chemotherapy regimens, are associated with dose-dependent cardiotoxicity. Exercise has been widely accepted as an effective intervention in reducing cardiovascular risk in a variety of different clinical conditions. However, the benefits of exercise in anthracycline-mediated cardiotoxicity are not clearly understood. First, this review discusses the pre-clinical studies which have elucidated the cardioprotective mechanisms of aerobic and resistance exercise in improving cardiovascular function in the setting of anthracycline treatment. Next, it aims to summarize the results of aerobic and resistance exercise clinical trials conducted in females with breast cancer who received anthracycline-based chemotherapy. The review further discusses the current exercise guidelines for women undergoing chemotherapy and contraindications for exercise. Finally, the review addresses gaps in research, specifically the need for further clinical trials to establish a recommended exercise prescription within this patient population.


Assuntos
Neoplasias da Mama , Sobreviventes de Câncer , Cardiopatias , Antraciclinas/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Feminino , Humanos
2.
Int J Cardiol ; 344: 170-178, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34563597

RESUMO

Immune-checkpoint inhibitors (ICIs), a unique antibody-based therapeutic strategy, have revolutionized the treatment landscape of solid and hematological cancers. Despite the proven benefits of ICIs, the cardiotoxicity from unspecific immune activation (uncommon but potentially fatal) is a continuing concern. Accumulating preclinical research has demonstrated that ICIs initiate inflammation in the myocardium, while clinically significant cardiotoxicity were reported in few patients receiving ICI therapy, probably due to the low incidence and unspecific symptoms. The subtle signs and symptoms (e.g., chest pain, dizziness, and dyspnea) were likely attributed to cancer and/or non-cardiac events by previous studies, thus limiting the understanding of the incidence, outcomes, risk factors, and management of ICI-related cardiotoxicity. The heterogeneous clinical presentation and complex diagnostic procedure further make it challenging to accurately identify ICI-related cardiac events in clinical trials. Therefore, ICI-related cardiotoxicity, whose incidence is probably underestimated, has not been well recognized. In this article, we provide an overview of potential mechanisms underlying ICI-related cardiotoxicity and review accumulating clinical evidence of ICI-related cardiotoxicity, with a focus on myocarditis. Moreover, we discuss possible strategies to manage ICI-related cardiotoxicity and highlight the importance of developing cardio-oncology.


Assuntos
Cardiotoxicidade , Neoplasias , Cardiotoxicidade/diagnóstico , Cardiotoxicidade/etiologia , Humanos , Inibidores de Checkpoint Imunológico , Imunoterapia , Neoplasias/tratamento farmacológico , Fatores de Risco
3.
Elife ; 102021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34338636

RESUMO

Drug-induced cardiotoxicity and hepatotoxicity are major causes of drug attrition. To decrease late-stage drug attrition, pharmaceutical and biotechnology industries need to establish biologically relevant models that use phenotypic screening to detect drug-induced toxicity in vitro. In this study, we sought to rapidly detect patterns of cardiotoxicity using high-content image analysis with deep learning and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). We screened a library of 1280 bioactive compounds and identified those with potential cardiotoxic liabilities in iPSC-CMs using a single-parameter score based on deep learning. Compounds demonstrating cardiotoxicity in iPSC-CMs included DNA intercalators, ion channel blockers, epidermal growth factor receptor, cyclin-dependent kinase, and multi-kinase inhibitors. We also screened a diverse library of molecules with unknown targets and identified chemical frameworks that show cardiotoxic signal in iPSC-CMs. By using this screening approach during target discovery and lead optimization, we can de-risk early-stage drug discovery. We show that the broad applicability of combining deep learning with iPSC technology is an effective way to interrogate cellular phenotypes and identify drugs that may protect against diseased phenotypes and deleterious mutations.


Assuntos
Cardiotoxicidade/etiologia , Aprendizado Profundo , Coração/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Miócitos Cardíacos/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos
4.
Redox Biol ; 46: 102089, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34364220

RESUMO

As a potent chemotherapeutic agent, doxorubicin (DOX) is widely used for the treatment of a variety of cancers However, its clinical utility is limited by dose-dependent cardiotoxicity, and pathogenesis has traditionally been attributed to the formation of reactive oxygen species (ROS). Accordingly, the prevention of DOX-induced cardiotoxicity is an indispensable goal to optimize therapeutic regimens and reduce morbidity. Acetylation is an emerging and important epigenetic modification regulated by histone deacetylases (HDACs) and histone acetyltransferases (HATs). Despite extensive studies of the molecular basis and biological functions of acetylation, the application of acetylation as a therapeutic target for cardiotoxicity is in the initial stage, and further studies are required to clarify the complex acetylation network and improve the clinical management of cardiotoxicity. In this review, we summarize the pivotal functions of HDACs and HATs in DOX-induced oxidative stress, the underlying mechanisms, the contributions of noncoding RNAs (ncRNAs) and exercise-mediated deacetylases to cardiotoxicity. Furthermore, we describe research progress related to several important SIRT activators and HDAC inhibitors with potential clinical value for chemotherapy and cardiotoxicity. Collectively, a comprehensive understanding of specific roles and recent developments of acetylation in doxorubicin-induced cardiotoxicity will provide a basis for improved treatment outcomes in cancer and cardiovascular diseases.


Assuntos
Cardiotoxicidade , Miócitos Cardíacos , Acetilação , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Doxorrubicina/efeitos adversos , Humanos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
5.
Cancer Treat Rev ; 100: 102282, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34438238

RESUMO

Immune checkpoint inhibitors (ICIs) and BRAF and MEK inhibitors (BRAFi/MEKi) have drastically improved the outcome of melanoma patients. ICIs can induce myocarditis, a rare immune related adverse event (irAE) with an estimated lethality of 50%. BRAFi/MEKi may induce left ventricular ejection fraction decrease, hypertension or QT interval prolongation. While the BRAFi/MEKi induced cardiotoxicity is often reversible upon treatment discontinuation or dose adaptation and symptomatic therapy is often sufficient to restore cardiac function, the treatment of ICI-induced myocarditis mainly relies on high dose corticosteroids. There is no established therapy for steroid resistant myocarditis, yet various drugs have been reported to improve outcome. Shared epitopes between melanoma cells and cardiac tissue are thought to underlie the development of ICIs induced myocarditis. The mechanism of BRAFi/MEKi induced cardiotoxicity appears to be related to the Ras-Raf-MEK-ERK pathway in cardiomyocyte repair, survival and proliferation. With the emerging application of ICI-BRAFi/MEKi combinations, so called triplet therapies, differentiating between these two types of cardiotoxicity will become important for appropriate patient management. In this article we provide a summary of the existing literature on the pathophysiology, diagnosis and management of cardiotoxicity of melanoma therapies.


Assuntos
Cardiotoxicidade/diagnóstico , Cardiotoxicidade/tratamento farmacológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Corticosteroides/uso terapêutico , Cardiotoxicidade/etiologia , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Miocardite/induzido quimicamente , Miocardite/diagnóstico , Miocardite/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
Toxicol Lett ; 350: 213-224, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34252509

RESUMO

The metal/metal alloy-based implants and prostheses are in use for over a century, and the rejections, revisions, and metal particle-based toxicities were reported concurrently. Complications developed due to metal ions, metal debris, and organo-metallic particles in orthopedic patients have been a growing concern in recent years. It was reported that local and systemic toxicity caused by such released products from the implants is one of the major reasons for implant rejection and revision. Even though the description of environmental metal toxicants and safety limits for their exposure to humans were well established in the literature, an effort was not adequately performed in the case of implant-based metal toxicology. Since the metal ion concentration in serum acts as a possible indicator of the systemic toxicity, this review summarizes the reported human serum safe limits, toxic limits, and concentration range (µg/L, ppb, etc.) for mild to severe symptoms of six (cardiac, hepatic, neuro, nephron, dermal and endocrine) systemic toxicities for twelve most commonly used metallic implants. It also covers the widely used metal ion quantification techniques and systemic toxicity treatments reported.


Assuntos
Cardiotoxicidade/etiologia , Intoxicação por Metais Pesados/etiologia , Íons/toxicidade , Metais/toxicidade , Próteses e Implantes/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Intoxicação por Metais Pesados/sangue , Humanos , Íons/sangue , Masculino , Metais/sangue , Pessoa de Meia-Idade
9.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299059

RESUMO

BACKGROUND: Doxorubicin (Dox) is a first-line treatment for triple negative breast cancer (TNBC), but its use may be limited by its cardiotoxicity mediated by the production of reactive oxygen species. We evaluated whether vitamin D may prevent Dox-induced cardiotoxicity in a mouse TNBC model. METHODS: Female Balb/c mice received rodent chow with vitamin D3 (1500 IU/kg; vehicle) or chow supplemented with additional vitamin D3 (total, 11,500 IU/kg). the mice were inoculated with TNBC tumors and treated with intraperitoneal Dox (6 or 10 mg/kg). Cardiac function was evaluated with transthoracic echocardiography. The cardiac tissue was evaluated with immunohistochemistry and immunoblot for levels of 4-hydroxynonenal, NAD(P)H quinone oxidoreductase (NQO1), C-MYC, and dynamin-related protein 1 (DRP1) phosphorylation. RESULTS: At 15 to 18 days, the mean ejection fraction, stroke volume, and fractional shortening were similar between the mice treated with vitamin D + Dox (10 mg/kg) vs. vehicle but significantly greater in mice treated with vitamin D + Dox (10 mg/kg) vs. Dox (10 mg/kg). Dox (10 mg/kg) increased the cardiac tissue levels of 4-hydroxynonenal, NQO1, C-MYC, and DRP1 phosphorylation at serine 616, but these increases were not observed with vitamin D + Dox (10 mg/kg). A decreased tumor volume was observed with Dox (10 mg/kg) and vitamin D + Dox (10 mg/kg). CONCLUSIONS: Vitamin D supplementation decreased Dox-induced cardiotoxicity by decreasing the reactive oxygen species and mitochondrial damage, and did not decrease the anticancer efficacy of Dox against TNBC.


Assuntos
Cardiotoxicidade/prevenção & controle , Citoproteção/efeitos dos fármacos , Doxorrubicina/toxicidade , Substâncias Protetoras/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Vitamina D/farmacologia , Vitaminas/farmacologia , Animais , Antibióticos Antineoplásicos/toxicidade , Cardiotoxicidade/etiologia , Cardiotoxicidade/patologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias de Mama Triplo Negativas/induzido quimicamente , Neoplasias de Mama Triplo Negativas/patologia
10.
Biomed Pharmacother ; 139: 111708, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243633

RESUMO

Doxorubicin (Dox) is a secondary metabolite of the mutated strain of Streptomyces peucetius var. Caesius and belongs to the anthracyclines family. The anti-cancer activity of Dox is mainly exerted through the DNA intercalation and inhibiting topoisomerase II enzyme in fast-proliferating tumors. However, Dox causes cumulative and dose-dependent cardiotoxicity, which results in increased risks of mortality among cancer patients and thus limiting its wide clinical applications. There are several mechanisms has been proposed for doxorubicin-induced cardiotoxicity and oxidative stress, free radical generation and apoptosis are most widely reported. Apart from this, other mechanisms are also involved in Dox-induced cardiotoxicity such as impaired mitochondrial function, a perturbation in iron regulatory protein, disruption of Ca2+ homeostasis, autophagy, the release of nitric oxide and inflammatory mediators and altered gene and protein expression that involved apoptosis. Dox also causes downregulation of DNA methyltransferase 1 (DNMT1) enzyme activity which leads to a reduction in the DNA methylation process. This hypomethylation causes dysregulation in the mitochondrial genes like peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1-alpha (PGC-1α), nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM) unit in the heart. Apart from DNA methylation, Dox treatment also alters the micro RNAs levels and histone deacetylase (HDAC) activity. Therefore, in the current review, we have provided a detailed update on the current understanding of the pathological mechanisms behind the well-known Dox-induced cardiotoxicity. Further, we have provided some of the most plausible pharmacological strategies which have been tested against Dox-induced cardiotoxicity.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Cardiotoxicidade/etiologia , Doxorrubicina/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Humanos , Mitocôndrias Cardíacas/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos
11.
Mol Med Rep ; 24(3)2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34296293

RESUMO

It has been shown that ferroptosis is involved in doxorubicin (DOX)­induced cardiotoxicity and that ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) can protect cardiomyocytes from ferroptosis. Thus, the present study aimed to investigate whether ENPP2 could protect cardiomyocytes from DOX­induced injury by inhibiting ferroptosis. H9c2 cardiomyocytes were exposed to various concentrations (0.625, 1.25, 2.5, 5 or 10 µM) of DOX for different time periods. Cell viability and ENPP2 expression were determined. ENPP2­overexpressing H9c2 cells were treated with DOX and subsequently cell viability, oxidative stress, autophagy and ferroptosis were measured using the corresponding assays (MTT assay, commercial kits and western blot analysis). Dual­luciferase reporter and chromatin immunoprecipitation assays, as well as bioinformatics analysis, were applied to detect the interaction between ENPP2 and FoxO4. Following FoxO4 overexpression in H9c2 cells, the aforementioned cellular processes were assessed. The results indicated that ENPP2 expression was downregulated following treatment of the cells with DOX. DOX also led to the decreased cell viability, reduced autophagy and elevated ferroptosis in H9c2 cells, which were notably reversed by ENPP2 overexpression. In addition, FoxO4 bound to the ENPP2 promoter, resulting in inhibition of its expression. Following FoxO4 overexpression in H9c2 cells, further experiments conducted using commercial kits and western blot analysis revealed that FoxO4 overexpression partially inhibited the effects of ENPP2 overexpression on DOX­induced oxidative stress, autophagy and ferroptosis in H9c2 cells. In conclusion, the data indicated that ENPP2 was transcriptionally regulated by FoxO4 to protect cardiomyocytes from DOX­induced toxicity by inhibiting ferroptosis. Therefore, specific treatment approaches targeting the FoxO4/ENPP2 axis and ferroptosis may provide potential therapies for alleviating DOX­induced cardiotoxicity.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Miócitos Cardíacos/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Doxorrubicina/toxicidade , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Fatores de Transcrição Forkhead/genética , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Diester Fosfórico Hidrolases/genética , Ratos , Ativação Transcricional
12.
Clin Sci (Lond) ; 135(14): 1649-1668, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34283204

RESUMO

In the past two decades, treatment outcomes for a wide range of malignancies have improved remarkably due to the development of novel anti-cancer therapies, including vascular endothelial growth factor inhibitors (VEGFIs) and immune checkpoint inhibitors (ICIs). Despite their unprecedented anti-tumour effects, it is becoming increasingly clear that both types of agents are associated with specific cardiovascular toxicity, including hypertension, congestive heart failure, myocarditis and acceleration of atherosclerosis. Currently, VEGFI and ICI combination therapy is recommended for the treatment of advanced renal cell carcinoma (RCC) and has shown promising treatment efficacy in other tumour types as well. Consequently, VEGFI and ICI combination therapy will most likely become an important therapeutic strategy for various malignancies. However, this combinatory approach is expected to be accompanied by a substantial increase in cardiovascular risk, as both types of agents could act synergistically to induce cardiovascular sequelae. Therefore, a comprehensive baseline assessment and adequate monitoring by specialised cardio-oncology teams is essential in case these agents are used in combination, particularly in high-risk patients. This review summarises the mechanisms of action and treatment indications for currently registered VEGFIs and ICIs, and discusses their main vascular and cardiac toxicity. Subsequently, we provide the biological rationales for the observed promising synergistic anti-tumour effects of combined VEGFI/ICI administration. Lastly, we speculate on the increased risk for cardiovascular toxicity in case these agents are used in combination and its implications and future directions for the clinical situation.


Assuntos
Inibidores da Angiogênese/efeitos adversos , Cardiotoxicidade/etiologia , Doenças Cardiovasculares/tratamento farmacológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores da Angiogênese/uso terapêutico , Fatores de Risco de Doenças Cardíacas , Humanos , Hipertensão/etiologia , Hipertensão/fisiopatologia , Inibidores de Checkpoint Imunológico/uso terapêutico
13.
Medicine (Baltimore) ; 100(23): e26318, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34115044

RESUMO

RATIONALE: Acute organophosphorus pesticide poisoning (AOPP) is a common critical illness observed in clinical practice, and severe AOPP can cause serious cardiac toxicity. PATIENT CONCERNS: This patient was a 43-year-old woman who was admitted to the emergency department with acute respiratory failure and hypotension 13 hours after oral consumption of 300 mL of phoxim pesticide. DIAGNOSES: Acute organophosphorus pesticide poisoning, cardiogenic shock. INTERVENTIONS: We conducted veno-arterial extracorporeal membrane oxygenation (VA-ECMO) therapy as the patient did not respond to conventional measures. OUTCOMES: This patient was successfully rescued with VA-ECMO therapy and discharged. LESSONS: We suggest that for patients with severe myocardial injury complicated with cardiogenic shock caused by AOPP, the use of VA-ECMO therapy can improve the prognosis.


Assuntos
Cardiotoxicidade , Oxigenação por Membrana Extracorpórea/métodos , Intoxicação por Organofosfatos/complicações , Praguicidas/toxicidade , Choque Cardiogênico , Adulto , Cardiotoxicidade/complicações , Cardiotoxicidade/etiologia , Cardiotoxicidade/fisiopatologia , Eletrocardiografia/métodos , Feminino , Humanos , Organofosfatos/toxicidade , Choque Cardiogênico/diagnóstico , Choque Cardiogênico/etiologia , Choque Cardiogênico/fisiopatologia , Choque Cardiogênico/terapia , Resultado do Tratamento
14.
Trends Pharmacol Sci ; 42(8): 675-687, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34092416

RESUMO

Cardiac physiology and homeostasis are maintained by the interaction of multiple cell types, via both intra- and intercellular signaling pathways. Perturbations in these signaling pathways induced by oncology therapies can reduce cardiac function, ultimately leading to heart failure. As cancer survival increases, related cardiovascular complications are becoming increasingly prevalent, thus identifying the perturbations and cell signaling drivers of cardiotoxicity is increasingly important. Here, we discuss the homotypic and heterotypic cellular interactions that form the basis of intra- and intercellular cardiac signaling pathways, and how oncological agents disrupt these pathways, leading to heart failure. We also highlight the emerging systems biology techniques that can be applied, enabling a deeper understanding of the intra- and intercellular signaling pathways across multiple cell types associated with cardiovascular toxicity.


Assuntos
Cardiopatias , Preparações Farmacêuticas , Cardiotoxicidade/etiologia , Humanos , Miócitos Cardíacos , Transdução de Sinais
15.
Life Sci ; 280: 119760, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34166713

RESUMO

Cardiotoxicity is a major side effect of the chemotherapeutic drug doxorubicin (Dox), which is further exacerbated when it is combined with trastuzumab, a standard care approach for Human Epidermal growth factor Receptor-type 2 (HER2) positive cancer patients. However, the molecular mechanisms of the underlying cardiotoxicity of this combination are still mostly elusive. Increased oxidative stress, impaired energetic substrate uses and topoisomerase IIB inhibition are among the biological processes proposed to explain Dox-induced cardiomyocyte dysfunction. Since cardiomyocytes express HER2, trastuzumab can also damage these cells by interfering with neuroregulin-1 signaling and mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/Akt and focal adhesion kinase (FAK)-dependent pathways. Nevertheless, Dox and trastuzumab target other cardiac cell types, such as endothelial cells, fibroblasts, cardiac progenitor cells and leukocytes, which can contribute to the clinical cardiotoxicity observed. This review aims to summarize the current knowledge on the cardiac signaling pathways modulated by these two antineoplastic drugs highly used in the management of breast cancer, not only focusing on cardiomyocytes but also to broaden the knowledge of the potential impact on other cells found in the heart.


Assuntos
Antineoplásicos/efeitos adversos , Cardiotoxicidade/etiologia , Doxorrubicina/efeitos adversos , Trastuzumab/efeitos adversos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Humanos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Neuregulina-1/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Receptor ErbB-2/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Nat Commun ; 12(1): 3279, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078883

RESUMO

Targeting the molecular pathways underlying the cardiotoxicity associated with thoracic irradiation and doxorubicin (Dox) could reduce the morbidity and mortality associated with these anticancer treatments. Here, we find that vascular endothelial cells (ECs) with persistent DNA damage induced by irradiation and Dox treatment exhibit a fibrotic phenotype (endothelial-mesenchymal transition, EndMT) correlating with the colocalization of L1CAM and persistent DNA damage foci. We demonstrate that treatment with the anti-L1CAM antibody Ab417 decreases L1CAM overexpression and nuclear translocation and persistent DNA damage foci. We show that in whole-heart-irradiated mice, EC-specific p53 deletion increases vascular fibrosis and the colocalization of L1CAM and DNA damage foci, while Ab417 attenuates these effects. We also demonstrate that Ab417 prevents cardiac dysfunction-related decrease in fractional shortening and prolongs survival after whole-heart irradiation or Dox treatment. We show that cardiomyopathy patient-derived cardiovascular ECs with persistent DNA damage show upregulated L1CAM and EndMT, indicating clinical applicability of Ab417. We conclude that controlling vascular DNA damage by inhibiting nuclear L1CAM translocation might effectively prevent anticancer therapy-associated cardiotoxicity.


Assuntos
Anticorpos Neutralizantes/farmacologia , Cardiomiopatias/prevenção & controle , Cardiotoxicidade/prevenção & controle , Doxorrubicina/toxicidade , Raios gama/efeitos adversos , Molécula L1 de Adesão de Célula Nervosa/genética , Animais , Antibióticos Antineoplásicos/toxicidade , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Cardiotoxicidade/etiologia , Cardiotoxicidade/genética , Cardiotoxicidade/metabolismo , Estudos de Casos e Controles , Técnicas de Cocultura , Dano ao DNA , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Células Endoteliais/efeitos da radiação , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos da radiação , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/efeitos da radiação , Molécula L1 de Adesão de Célula Nervosa/antagonistas & inibidores , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética
20.
ESC Heart Fail ; 8(4): 2397-2418, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33955207

RESUMO

The most common cancer diagnosis in female population is breast cancer, which affects every year about 2.0 million women worldwide. In recent years, significant progress has been made in oncological therapy, in systemic treatment, and in radiotherapy of breast cancer. Unfortunately, the improvement in the effectiveness of oncological treatment and prolonging patients' life span is associated with more frequent occurrence of organ complications, which are side effects of this treatment. Current recommendations suggest a periodic monitoring of the cardiovascular system in course of oncological treatment. The monitoring includes the assessment of occurrence of risk factors for cardiovascular diseases in combination with the evaluation of the left ventricular systolic function using echocardiography and electrocardiography as well as with the analysis of the concentration of cardiac biomarkers. The aim of this review was critical assessment of the breast cancer therapy cardiotoxicity and the analysis of methods its detections. The new cardio-specific biomarkers in serum, the development of modern imaging techniques (Global Longitudinal Strain and Three-Dimensional Left Ventricular Ejection Fraction) and genotyping, and especially their combined use, may become a useful tool for identifying patients at risk of developing cardiotoxicity, who require further cardiovascular monitoring or cardioprotective therapy.


Assuntos
Neoplasias da Mama , Cardiopatias , Neoplasias da Mama/diagnóstico , Cardiotoxicidade/diagnóstico , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Feminino , Cardiopatias/induzido quimicamente , Cardiopatias/diagnóstico , Cardiopatias/epidemiologia , Humanos , Volume Sistólico , Função Ventricular Esquerda
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