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1.
Cell ; 169(1): 132-147.e16, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28340339

RESUMO

The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density, and renal function in both fast aging XpdTTD/TTD and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored.


Assuntos
Envelhecimento/patologia , Antibióticos Antineoplásicos/efeitos adversos , Peptídeos Penetradores de Células/farmacologia , Doxorrubicina/efeitos adversos , Envelhecimento/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacologia , Apoptose , Proteínas de Ciclo Celular , Linhagem Celular , Sobrevivência Celular , Senescência Celular/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Feminino , Fibroblastos/citologia , Fatores de Transcrição Forkhead/química , Fatores de Transcrição Forkhead/metabolismo , Humanos , Corpos de Inclusão/efeitos dos fármacos , Corpos de Inclusão/metabolismo , Corpos de Inclusão/patologia , Rim/efeitos dos fármacos , Rim/fisiologia , Fígado/efeitos dos fármacos , Fígado/fisiologia , Masculino , Camundongos , Síndromes de Tricotiodistrofia/tratamento farmacológico , Proteína Supressora de Tumor p53/metabolismo
2.
PLoS Genet ; 20(2): e1011164, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38416769

RESUMO

TOP2 inhibitors (TOP2i) are effective drugs for breast cancer treatment. However, they can cause cardiotoxicity in some women. The most widely used TOP2i include anthracyclines (AC) Doxorubicin (DOX), Daunorubicin (DNR), Epirubicin (EPI), and the anthraquinone Mitoxantrone (MTX). It is unclear whether women would experience the same adverse effects from all drugs in this class, or if specific drugs would be preferable for certain individuals based on their cardiotoxicity risk profile. To investigate this, we studied the effects of treatment of DOX, DNR, EPI, MTX, and an unrelated monoclonal antibody Trastuzumab (TRZ) on iPSC-derived cardiomyocytes (iPSC-CMs) from six healthy females. All TOP2i induce cell death at concentrations observed in cancer patient serum, while TRZ does not. A sub-lethal dose of all TOP2i induces limited cellular stress but affects calcium handling, a function critical for cardiomyocyte contraction. TOP2i induce thousands of gene expression changes over time, giving rise to four distinct gene expression response signatures, denoted as TOP2i early-acute, early-sustained, and late response genes, and non-response genes. There is no drug- or AC-specific signature. TOP2i early response genes are enriched in chromatin regulators, which mediate AC sensitivity across breast cancer patients. However, there is increased transcriptional variability between individuals following AC treatments. To investigate potential genetic effects on response variability, we first identified a reported set of expression quantitative trait loci (eQTLs) uncovered following DOX treatment in iPSC-CMs. Indeed, DOX response eQTLs are enriched in genes that respond to all TOP2i. Next, we identified 38 genes in loci associated with AC toxicity by GWAS or TWAS. Two thirds of the genes that respond to at least one TOP2i, respond to all ACs with the same direction of effect. Our data demonstrate that TOP2i induce thousands of shared gene expression changes in cardiomyocytes, including genes near SNPs associated with inter-individual variation in response to DOX treatment and AC-induced cardiotoxicity.


Assuntos
Antraciclinas , Cardiotoxicidade , Humanos , Feminino , Antraciclinas/efeitos adversos , Antraciclinas/metabolismo , Cardiotoxicidade/genética , Cardiotoxicidade/metabolismo , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/metabolismo , Inibidores da Topoisomerase II/metabolismo , Inibidores da Topoisomerase II/farmacologia , Doxorrubicina/efeitos adversos , Doxorrubicina/metabolismo , Mitoxantrona/efeitos adversos , Mitoxantrona/metabolismo , Miócitos Cardíacos/metabolismo , Daunorrubicina/metabolismo , Daunorrubicina/farmacologia , Epirubicina/metabolismo , Epirubicina/farmacologia , DNA Topoisomerases Tipo II/genética , Expressão Gênica
3.
Eur Heart J ; 45(25): 2235-2250, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38607560

RESUMO

BACKGROUND AND AIMS: Patients with acute myeloid leukaemia (AML) suffer from severe myocardial injury during daunorubicin (DNR)-based chemotherapy and are at high risk of cardiac mortality. The crosstalk between tumour cells and cardiomyocytes might play an important role in chemotherapy-related cardiotoxicity, but this has yet to be demonstrated. This study aimed to identify its underlying mechanism and explore potential therapeutic targets. METHODS: Cardiac tissues were harvested from an AML patient after DNR-based chemotherapy and were subjected to single-nucleus RNA sequencing. Cardiac metabolism and function were evaluated in AML mice after DNR treatment by using positron emission tomography, magnetic resonance imaging, and stable-isotope tracing metabolomics. Plasma cytokines were screened in AML mice after DNR treatment. Genetically modified mice and cell lines were used to validate the central role of the identified cytokine and explore its downstream effectors. RESULTS: In the AML patient, disruption of cardiac metabolic homeostasis was associated with heart dysfunction after DNR-based chemotherapy. In AML mice, cardiac fatty acid utilization was attenuated, resulting in cardiac dysfunction after DNR treatment, but these phenotypes were not observed in similarly treated tumour-free mice. Furthermore, tumour cell-derived interleukin (IL)-1α was identified as a primary factor leading to DNR-induced cardiac dysfunction and administration of an anti-IL-1α neutralizing antibody could improve cardiac functions in AML mice after DNR treatment. CONCLUSIONS: This study revealed that crosstalk between tumour cells and cardiomyocytes during chemotherapy could disturb cardiac energy metabolism and impair heart function. IL-1α neutralizing antibody treatment is a promising strategy for alleviating chemotherapy-induced cardiotoxicity in AML patients.


Assuntos
Daunorrubicina , Interleucina-1alfa , Leucemia Mieloide Aguda , Animais , Leucemia Mieloide Aguda/tratamento farmacológico , Humanos , Interleucina-1alfa/metabolismo , Camundongos , Cardiotoxicidade/etiologia , Antibióticos Antineoplásicos/efeitos adversos , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo
4.
J Mol Cell Cardiol ; 186: 81-93, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37995517

RESUMO

AIM: Doxorubicin-induced cardiotoxicity (DIC) is an increasing problem, occurring in many cancer patients receiving anthracycline chemotherapy, ultimately leading to heart failure (HF). Unfortunately, DIC remains difficult to manage due to an ignorance regarding pathophysiological mechanisms. Our work aimed to evaluate the role of HSP47 in doxorubicin-induced HF, and to explore the molecular mechanisms. METHODS AND RESULTS: Mice were exposed to multi-intraperitoneal injection of doxorubicin (DOX, 4mg/kg/week, for 6 weeks continuously) to produce DIC. HSP47 expression was significantly upregulated in serum and in heart tissue in DOX-treated mice and in isolated cardiomyocytes. Mice with cardiac-specific HSP47 overexpression and knockdown were generated using recombinant adeno-associated virus (rAVV9) injection. Importantly, cardiac-specific HSP47 overexpression exacerbated cardiac dysfunction in DIC, while HSP47 knockdown prevented DOX-induced cardiac dysfunction, cardiac atrophy and fibrosis in vivo and in vitro. Mechanistically, we identified that HSP47 directly interacted with IRE1α in cardiomyocytes. Furthermore, we provided powerful evidence that HSP47-IRE1α complex promoted TXNIP/NLRP3 inflammasome and reinforced USP1-mediated NLRP3 ubiquitination. Moreover, NLRP3 deficiency in vivo conspicuously abolished HSP47-mediated cardiac atrophy and fibrogenesis under DOX condition. CONCLUSION: HSP47 was highly expressed in serum and cardiac tissue after doxorubicin administration. HSP47 contributed to long-term anthracycline chemotherapy-associated cardiac dysfunction in an NLRP3-dependent manner. HSP47 therefore represents a plausible target for future therapy of doxorubicin-induced HF.


Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Camundongos , Humanos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas de Choque Térmico HSP47/metabolismo , Cardiotoxicidade/metabolismo , Doxorrubicina/farmacologia , Endorribonucleases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Miócitos Cardíacos/metabolismo , Antibióticos Antineoplásicos/efeitos adversos , Atrofia/induzido quimicamente , Atrofia/metabolismo , Atrofia/patologia , Apoptose , Estresse Oxidativo
5.
Pflugers Arch ; 476(5): 797-808, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38368293

RESUMO

A common anthracycline antibiotic used to treat cancer patients is doxorubicin (DOX). One of the effects of DOX therapy is skeletal muscle fatigue. Our goal in this research was to study the beneficial effect of exercise on DOX-induced damaged muscle fibers and compare the effect of different exercise strategies (prophylactic, post- toxicity and combined) on DOX toxicity. Five groups were created from 40 male rats: group I, control group; group II, DOX was administered intraperitoneally for 2 weeks over 6 equal injections (each 2.5 mg/kg); group III, rats trained for 3 weeks before DOX; group IV, rats trained for 8 weeks after DOX; and group V, rats were trained for 3 weeks before DOX followed by 8 weeks after. Measures of oxidative damage (H2O2, catalase), inflammation (TNF-α), and glucose transporter 4 (GLUT4) expression on skeletal muscle were assessed. Also, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was estimated. Skeletal performance was evaluated by contraction time (CT), half relaxation time (1/2 RT), and force-frequency relationship by the end of this research. The current study demonstrated a detrimental effect of DOX on skeletal performance as evidenced by a significant increase in CT and 1/2 RT compared to control; in addition, H2O2, TNF-α, and HOMA-IR were significantly increased with a significant decrease in GLUT4 expression and catalase activity. Combined exercise therapy showed a remarkable improvement in skeletal muscle performance, compared to DOX, CT, and 1/2 RT which were significantly decreased; H2O2 and TNF-α were significantly decreased unlike catalase antioxidant activity that significantly increased; in addition, skeletal muscle glucose metabolism was significantly improved as GLUT4 expression significantly increased and HOMA-IR was significantly decreased. Exercise therapy showed significant improvement in all measured parameters relative to DOX. However, combined exercise therapy showed the best improvement relative to both pre-exercise and post-exercise groups.


Assuntos
Doxorrubicina , Transportador de Glucose Tipo 4 , Músculo Esquelético , Condicionamento Físico Animal , Animais , Masculino , Ratos , Antibióticos Antineoplásicos/toxicidade , Antibióticos Antineoplásicos/efeitos adversos , Catalase/metabolismo , Doxorrubicina/toxicidade , Doxorrubicina/efeitos adversos , Transportador de Glucose Tipo 4/metabolismo , Peróxido de Hidrogênio/metabolismo , Resistência à Insulina , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Doenças Musculares/induzido quimicamente , Doenças Musculares/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Condicionamento Físico Animal/métodos , Condicionamento Físico Animal/fisiologia , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
6.
Apoptosis ; 29(5-6): 816-834, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38281279

RESUMO

Doxorubicin (DOX) is an anthracycline antibiotic used as an antitumor treatment. However, its clinical application is limited due to severe side effects such as cardiotoxicity. In recent years, numerous studies have demonstrated that cellular aging has become a therapeutic target for DOX-induced cardiomyopathy. However, the underlying mechanism and specific molecular targets of DOX-induced cardiomyocyte aging remain unclear. Poly (ADP-ribose) polymerase (PARP) is a family of protein post-translational modification enzymes in eukaryotic cells, including 18 members. PARP-1, the most well-studied member of this family, has become a potential molecular target for the prevention and treatment of various cardiovascular diseases, such as DOX cardiomyopathy and heart failure. PARP-1 and PARP-2 share 69% homology in the catalytic regions. However, they do not entirely overlap in function. The role of PARP-2 in cardiovascular diseases, especially in DOX-induced cardiomyocyte aging, is less studied. In this study, we found for the first time that down-regulation of PARP-2 can inhibit DOX-induced cellular aging in cardiomyocytes. On the contrary, overexpression of PARP-2 can aggravate DOX-induced cardiomyocyte aging and injury. Further research showed that PARP-2 inhibited the expression and activity of SIRT1, which in turn was involved in the development of DOX-induced cardiomyocyte aging and injury. Our findings provide a preliminary experimental basis for establishing PARP-2 as a new target for preventing and treating DOX cardiomyopathy and related drug development.


Assuntos
Senescência Celular , Doxorrubicina , Miócitos Cardíacos , Poli(ADP-Ribose) Polimerases , Sirtuína 1 , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Miócitos Cardíacos/metabolismo , Sirtuína 1/metabolismo , Sirtuína 1/genética , Animais , Senescência Celular/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/metabolismo , Poli(ADP-Ribose) Polimerases/genética , Ratos , Cardiotoxicidade/patologia , Cardiotoxicidade/metabolismo , Cardiotoxicidade/prevenção & controle , Cardiotoxicidade/etiologia , Apoptose/efeitos dos fármacos , Ratos Sprague-Dawley , Antibióticos Antineoplásicos/toxicidade , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/farmacologia , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/patologia , Cardiomiopatias/metabolismo , Cardiomiopatias/genética , Humanos
7.
Pharmacogenomics J ; 24(4): 21, 2024 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-38951505

RESUMO

There is a known genetic susceptibility to anthracycline-induced cardiac dysfunction in childhood cancer survivors, but this has not been adequately shown in adolescent and young adult (AYA) patients. Our aim was to determine if the previously identified variants associated with cardiac dysfunction in childhood cancer patients affect AYA cancer patients similarly. Forty-five variants were selected for analysis in 253 AYAs previously treated with anthracyclines. We identified four variants that were associated with cardiac dysfunction: SLC10A2:rs7319981 (p = 0.017), SLC22A17:rs4982753 (p = 0.019), HAS3:rs2232228 (p = 0.023), and RARG:rs2229774 (p = 0.050). HAS3:rs2232228 and SLC10A2:rs7319981 displayed significant effects in our AYA cancer survivor population that were in the opposite direction than that reported in childhood cancer survivors. Genetic variants in the host genes were further analyzed for additional associations with cardiotoxicity in AYA cancer survivors. The host genes were then evaluated in a panel of induced pluripotent stem cell-derived cardiomyocytes to assess changes in levels of expression when treated with doxorubicin. Significant upregulation of HAS3 and SLC22A17 expression was observed (p < 0.05), with non-significant anthracycline-responsivity observed for RARG. Our study demonstrates that there is a genetic influence on cardiac dysfunction in AYA cancer patients, but there may be a difference in the role of genetics between childhood and AYA cancer survivors.


Assuntos
Antraciclinas , Sobreviventes de Câncer , Cardiotoxicidade , Predisposição Genética para Doença , Humanos , Adolescente , Antraciclinas/efeitos adversos , Adulto Jovem , Masculino , Feminino , Cardiotoxicidade/genética , Adulto , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Cardiopatias/induzido quimicamente , Cardiopatias/genética , Antibióticos Antineoplásicos/efeitos adversos , Fatores de Risco
8.
Clin Genet ; 105(2): 115-129, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-37961936

RESUMO

Anthracyclines remain the cornerstone of numerous chemotherapeutic protocols, with beneficial effects against haematological malignancies and solid tumours. Unfortunately, the clinical usefulness of anthracyclines is compromised by the development of cardiotoxic side effects, leading to dose limitations or treatment discontinuation. There is no absolute linear correlation between the incidence of cardiotoxicity and the threshold dose, suggesting that genetic factors may modify the association between anthracyclines and cardiotoxicity risk. And the majority of single nucleotide polymorphisms (SNPs) associated with anthracycline pharmacogenomics were identified in the ATP-binding cassette (ABC) and solute carrier (SLC) transporters, generating increasing interest in the pharmacogenetic implications of their genetic variations for anthracycline-induced cardiotoxicity (AIC). This review focuses on the influence of SLC and ABC polymorphisms on AIC and highlights the prospects and clinical significance of pharmacogenetics for individualised preventive approaches.


Assuntos
Antraciclinas , Cardiotoxicidade , Humanos , Cardiotoxicidade/genética , Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Proteínas de Membrana Transportadoras/genética , Polimorfismo de Nucleotídeo Único
9.
Heart Fail Rev ; 29(5): 969-988, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38990214

RESUMO

Cancer is the leading cause of death worldwide, and the number of cancer-related deaths is expected to increase. Common types of cancer include skin, breast, lung, prostate, and colorectal cancers. While clinical research has improved cancer therapies, these treatments often come with significant side effects such as chronic fatigue, hair loss, and nausea. In addition, cancer treatments can cause long-term cardiovascular complications. Doxorubicin (DOX) therapy is one example, which can lead to decreased left ventricle (LV) echocardiography (ECHO) parameters, increased oxidative stress in cellular level, and even cardiac fibrosis. The apelinergic system, specifically apelin and its receptor, together, has shown properties that could potentially protect the heart and mitigate the damages caused by DOX anti-cancer treatment. Studies have suggested that stimulating the apelinergic system may have therapeutic benefits for heart damage induced by DOX. Further research in chronic preclinical models is needed to confirm this hypothesis and understand the mechanism of action for the apelinergic system. This review aims to collect and present data on the effects of the apelinergic system on doxorubicin-induced cardiotoxicity.


Assuntos
Antibióticos Antineoplásicos , Apelina , Cardiotoxicidade , Doxorrubicina , Humanos , Doxorrubicina/efeitos adversos , Cardiotoxicidade/etiologia , Antibióticos Antineoplásicos/efeitos adversos , Apelina/metabolismo , Animais , Estresse Oxidativo/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Receptores de Apelina/metabolismo
10.
Nutr Cancer ; 76(10): 952-962, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38994569

RESUMO

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer in the world. Doxorubicin (Dox) is a very useful drug in these patients, however, one of the main adverse effects caused by the use of Dox is cardiotoxicity (CT). Protein-calorie malnutrition (PCM) is a factor that, among others, can influence the development of CT due to Dox. The aim of our study was to associate PCM as a risk factor for CT induced by Dox in Mexican children with ALL. We included 89 children with ALL who were treated with Dox, from October 2018 to July 2023, and of whom 14 developed some type of CT, 15 were underweight and 3 were overweight. The analysis of the association risk of CT due to PCM shows a statistically significant association of risk of developing CT due to PCM. On the other hand, healthy weight was associated with protection for developing CT due to Dox use. Of the total number of girls who presented CT, all had systolic dysfunction, while 6 of them also had diastolic dysfunction. On the other hand, of the total number of boys who presented CT, all of them had systolic dysfunction and only one of them also had diastolic dysfunction. These results show that in patients in which Dox is being administered, special attention is suggested for girls with PCM, since systolic failure is a precursor and occurs before diastolic failure in girls with PCM.


Assuntos
Cardiotoxicidade , Doxorrubicina , Estado Nutricional , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Doxorrubicina/efeitos adversos , Feminino , Masculino , Criança , Cardiotoxicidade/etiologia , México , Fatores de Risco , Pré-Escolar , Antibióticos Antineoplásicos/efeitos adversos , Adolescente , Lactente
11.
Eur Radiol ; 34(1): 226-235, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37552260

RESUMO

OBJECTIVES: To evaluate the early prevalence of anthracycline-induced cardiotoxicity (AIC) and anthracycline-induced liver injury (AILI) using T2 and T2* mapping and to explore their correlations. MATERIALS AND METHODS: The study included 17 cardiotoxic rabbits that received weekly injections of doxorubicin and magnetic resonance imaging (MRI) every 2 weeks for 10 weeks. Cardiac function and T2 and T2* values were measured on each period. Histopathological examinations for two to five rabbits were performed after each MRI scan. The earliest sensitive time and the threshold of MRI parameters for detecting AIC and AILI based on these MRI parameters were obtained. Moreover, the relationship between myocardial and liver damage was assessed. RESULTS: Early AIC could be detected by T2 mapping as early as the second week and focused on the 7th, 11th, and 12th segments of left ventricle. The cutoff value of 46.64 for the 7th segment had the best diagnostic value, with an area under the curve (of 0.767, sensitivity of 100%, and specificity of 52%. T2* mapping could detect the change in iron content for early AIC at the middle interventricular septum and AILI as early as the sixth week (p = 0.014, p = 0.027). The T2* values of the middle interventricular septum showed a significant positive association with the T2* values of the liver (r = 0.39, p = 0.002). CONCLUSION: T2 and T2* mapping showed value one-stop assessment of AIC and AILI and could obtain the earliest MRI diagnosis point and optimal parameter thresholds for these conditions. CLINICAL RELEVANCE STATEMENT: Anthracycline-induced cardiotoxicity could be detected by T2 mapping as earlier as the second week, mainly focusing on the 7th, 11th, and 12th segments of left ventricle. Combined with T2* mapping, hepatoxicity and supplementary cardiotoxicity were assessed by one-stop scan. KEY POINTS: • MRI screening time of cardiotoxicity was as early as the second week with focusing on T2 values of the 7th, 11th, and 12th segments of left ventricle. • T2* mapping could be used as a complement to T2 mapping to evaluate cardiotoxicity and as an effective index to detect iron change in the early stages of chemotherapy. • The T2* values of the middle interventricular septum showed a significant positive association with the T2* values of the liver, indicating that iron content in the liver and heart increased with an increase in the chemotherapeutic drugs.


Assuntos
Antraciclinas , Antibióticos Antineoplásicos , Cardiotoxicidade , Doxorrubicina , Animais , Coelhos , Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Cardiotoxicidade/diagnóstico por imagem , Cardiotoxicidade/tratamento farmacológico , Ferro , Fígado/diagnóstico por imagem , Doxorrubicina/uso terapêutico
12.
Inflamm Res ; 73(10): 1781-1801, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39180691

RESUMO

OBJECTIVE: Intestinal mucositis is one of the common side effects of anti-cancer chemotherapy. However, the molecular mechanisms involved in mucositis development remain incompletely understood. In this study, we investigated the function of receptor-interacting protein kinase 3 (RIP3/RIPK3) in regulating doxorubicin-induced intestinal mucositis and its potential mechanisms. METHODS: Intestinal mucositis animal models were induced in mice for in vivo studies. Rat intestinal cell line IEC-6 was used for in vitro studies. RNA­seq was used to explore the transcriptomic changes in doxorubicin-induced intestinal mucositis. Intact glycopeptide characterization using mass spectrometry was applied to identify α-1,2-fucosylated proteins associated with mucositis. RESULTS: Doxorubicin treatment increased RIP3 expression in the intestine and caused severe intestinal mucositis in the mice, depletion of RIP3 abolished doxorubicin-induced intestinal mucositis. RIP3-mediated doxorubicin-induced mucositis did not depend on mixed lineage kinase domain-like (MLKL) but on α-1,2-fucosyltransferase 2 (FUT2)-catalyzed α-1,2-fucosylation on inflammation-related proteins. Deficiency of MLKL did not affect intestinal mucositis, whereas inhibition of α-1,2-fucosylation by 2-deoxy-D-galactose (2dGal) profoundly attenuated doxorubicin-induced inflammation and mucositis. CONCLUSIONS: RIP3-FUT2 pathway is a central node in doxorubicin-induced intestinal mucositis. Targeting intestinal RIP3 and/or FUT2-mediated α-1,2-fucosylation may provide potential targets for preventing chemotherapy-induced intestinal mucositis.


Assuntos
Doxorrubicina , Fucosiltransferases , Galactosídeo 2-alfa-L-Fucosiltransferase , Camundongos Endogâmicos C57BL , Mucosite , Proteína Serina-Treonina Quinases de Interação com Receptores , Animais , Doxorrubicina/efeitos adversos , Mucosite/induzido quimicamente , Mucosite/metabolismo , Mucosite/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Fucosiltransferases/genética , Fucosiltransferases/metabolismo , Ratos , Linhagem Celular , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Camundongos , Antibióticos Antineoplásicos/toxicidade , Antibióticos Antineoplásicos/efeitos adversos , Camundongos Knockout
13.
J Cardiovasc Magn Reson ; 26(1): 101033, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38460840

RESUMO

BACKGROUND: Left ventricular ejection fraction (LVEF) is the most commonly clinically used imaging parameter for assessing cancer therapy-related cardiac dysfunction (CTRCD). However, LVEF declines may occur late, after substantial injury. This study sought to investigate cardiovascular magnetic resonance (CMR) imaging markers of subclinical cardiac injury in a miniature swine model. METHODS: Female Yucatan miniature swine (n = 14) received doxorubicin (2 mg/kg) every 3 weeks for 4 cycles. CMR, including cine, tissue characterization via T1 and T2 mapping, and late gadolinium enhancement (LGE) were performed on the same day as doxorubicin administration and 3 weeks after the final chemotherapy cycle. In addition, magnetic resonance spectroscopy (MRS) was performed during the 3 weeks after the final chemotherapy in 7 pigs. A single CMR and MRS exam were also performed in 3 Yucatan miniature swine that were age- and weight-matched to the final imaging exam of the doxorubicin-treated swine to serve as controls. CTRCD was defined as histological early morphologic changes, including cytoplasmic vacuolization and myofibrillar loss of myocytes, based on post-mortem analysis of humanely euthanized pigs after the final CMR exam. RESULTS: Of 13 swine completing 5 serial CMR scans, 10 (77%) had histological evidence of CTRCD. Three animals had neither histological evidence nor changes in LVEF from baseline. No absolute LVEF <40% or LGE was observed. Native T1, extracellular volume (ECV), and T2 at 12 weeks were significantly higher in swine with CTRCD than those without CTRCD (1178 ms vs. 1134 ms, p = 0.002, 27.4% vs. 24.5%, p = 0.03, and 38.1 ms vs. 36.4 ms, p = 0.02, respectively). There were no significant changes in strain parameters. The temporal trajectories in native T1, ECV, and T2 in swine with CTRCD showed similar and statistically significant increases. At the same time, there were no differences in their temporal changes between those with and without CTRCD. MRS myocardial triglyceride content substantially differed among controls, swine with and without CTRCD (0.89%, 0.30%, 0.54%, respectively, analysis of variance, p = 0.01), and associated with the severity of histological findings and incidence of vacuolated cardiomyocytes. CONCLUSION: Serial CMR imaging alone has a limited ability to detect histologic CTRCD beyond LVEF. Integrating MRS myocardial triglyceride content may be useful for detection of early potential CTRCD.


Assuntos
Cardiotoxicidade , Modelos Animais de Doenças , Doxorrubicina , Imagem Cinética por Ressonância Magnética , Miocárdio , Valor Preditivo dos Testes , Volume Sistólico , Porco Miniatura , Função Ventricular Esquerda , Animais , Feminino , Miocárdio/patologia , Miocárdio/metabolismo , Suínos , Função Ventricular Esquerda/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos , Fatores de Tempo , Espectroscopia de Ressonância Magnética , Antibióticos Antineoplásicos/efeitos adversos , Meios de Contraste , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/metabolismo
14.
J Pharmacol Sci ; 156(1): 9-18, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39068035

RESUMO

Necroptosis, necrosis characterized by RIPK3-MLKL activation, has been proposed as a mechanism of doxorubicin (DOX)-induced cardiomyopathy. We showed that rapamycin, an mTORC1 inhibitor, attenuates cardiomyocyte necroptosis. Here we examined role of MLKL in DOX-induced myocardial damage and protective effects of rapamycin. Cardiomyopathy was induced in mice by intraperitoneal injections of DOX (10 mg/kg, every other day) and followed for 7 days. DOX-treated mice showed a significant decline in LVEF assessed by cardiac MRI (45.5 ± 5.1% vs. 65.4 ± 4.2%), reduction in overall survival rates, and increases in myocardial RIPK3 and MLKL expression compared with those in vehicle-treated mice, and those changes were prevented by administration of rapamycin (0.25 mg/kg) before DOX injection. In immunohistochemical analyses, p-MLKL signals were detected in the cardiomyocytes of DOX-treated mice, and the signals were reduced by rapamycin. Mlkl+/- and Mlkl-/- mice were similarly resistant to DOX-induced cardiac dysfunction, indicating that a modest reduction in MLKL level is sufficient to prevent the development of DOX-induced cardiomyopathy. However, evidence of cardiomyocyte necrosis assessed by C9 immunostaining, presence of replacement fibrosis, and electron microscopic analyses was negligible in the myocardium of DOX-treated mice. Thus, MLKL-mediated signaling contributes to DOX-induced cardiac dysfunction primarily by a necrosis-independent mechanism, which is inhibitable by rapamycin.


Assuntos
Cardiomiopatias , Doxorrubicina , Camundongos Endogâmicos C57BL , Miócitos Cardíacos , Necroptose , Proteínas Quinases , Proteína Serina-Treonina Quinases de Interação com Receptores , Sirolimo , Animais , Doxorrubicina/efeitos adversos , Proteínas Quinases/metabolismo , Sirolimo/farmacologia , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/prevenção & controle , Cardiomiopatias/patologia , Cardiomiopatias/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Necroptose/efeitos dos fármacos , Masculino , Camundongos , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/toxicidade
15.
J Biochem Mol Toxicol ; 38(10): e23855, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39328005

RESUMO

Adriamycin is an anticancer anthracycline drug that inhibits the progression of topoisomerase II activity and causes apoptosis. The effective clinical application of the drug is very much limited by its adverse drug reactions on various tissues. Most importantly, Adriamycin causes cardiomyopathy, one of the life-threatening complications of the drug. Altered expression of PPARγ in adipocytes inhibited the glucose and fatty acids uptake by down regulating GLUT4 and CD36 expression and causes cardiotoxicity. Therefore, the influence of Adriamycin in cardiac ailments was investigated in vivo and in vitro. Adriamycin treated rats showed altered ECG profile, arrhythmic heartbeat with the elevated levels of CRP and LDH. Dysregulated lipid profiles with elevated levels of cholesterol and triglycerides were also observed. Possibilities of cardiac problems due to cardiomyopathy were analyzed through histopathology. Adriamycin treated rats showed no signs for atheromatous plaque formation in aorta but disorganized cardiomyocytes with myofibrillar loss and inflammation in heart tissue, indicative of cardiomyopathy. Reduced levels of antioxidant enzymes confirmed the incidence of oxidative stress. Adriamycin treatment significantly reduced glucose and insulin levels, creating energy demand due to decreased glucose and insulin levels with increased fatty acid accumulation, ultimately resulting in oxidative stress mediated cardiomyopathy. Since PPARs play a vital role in regulating oxidative stress, the effect of Adriamycin on PPARγ was analyzed by western blot. Adriamycin downregulated PPARγ in a dose-dependent manner in H9C2 cells in vitro. Overall, our study suggests that Adriamycin alters glucose and lipid metabolism via PPARγ inhibition that leads to oxidative stress and cardiomyopathy that necessitates a different therapeutic approach.


Assuntos
Cardiomiopatias , Doxorrubicina , PPAR gama , Animais , Masculino , Ratos , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/toxicidade , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Linhagem Celular , Doxorrubicina/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/antagonistas & inibidores , PPAR gama/metabolismo , Ratos Wistar
16.
J Biochem Mol Toxicol ; 38(10): e23861, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39305037

RESUMO

Doxorubicin (DOX) is an anthracycline antibiotic widely employed to treat carcinoma. Nevertheless, severe cardiotoxic side effects restrict its clinical use. Esculetin, a natural flavonoid, is found abundantly in plants. This study evaluated the protective effects of esculetin against DOX-induced hepatotoxicity in rat livers. Forty-eight rats were randomly divided into six groups with eight rats in each group: control (I), DOX (II), esculetin (III, 50 mg/kg), esculetin (IV, 100 mg/kg), DOX+esculetin 50 (V, DOX+esculetin 50 mg/kg), and DOX+esculetin 100 (VI, DOX+esculetin 100 mg/kg). The administration of esculetin effectively mitigated alterations in the measured biochemical parameters induced by DOX. Gene expression analyses demonstrated that esculetin treatment significantly reduced the DOX-induced expression of Foxo1, Hspa1a, Hsp4a, Hsp5a, Casp3, and Casp9 while increasing the DOX-induced expression of Foxo3. These findings suggest that esculetin, with its antioxidant and anti-inflammatory effects, might be a therapeutic option for protecting against DOX-induced hepatotoxicity.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Doxorrubicina , Umbeliferonas , Animais , Doxorrubicina/efeitos adversos , Doxorrubicina/toxicidade , Umbeliferonas/farmacologia , Ratos , Masculino , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/genética , Fatores de Transcrição Forkhead/metabolismo , Caspases/metabolismo , Antibióticos Antineoplásicos/toxicidade , Antibióticos Antineoplásicos/efeitos adversos , Transdução de Sinais/efeitos dos fármacos
17.
BMC Cardiovasc Disord ; 24(1): 260, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38769516

RESUMO

INTRODUCTION: Use of doxorubicin, an anthracycline chemotherapeutic agent has been associated with late-occurring cardiac toxicities. Detection of early-occurring cardiac effects of cancer chemotherapy is essential to prevent occurrence of adverse events including toxicity, myocardial dysfunction, and death. OBJECTIVE: To investigate the prevalence of elevated cardiac troponin T (cTnT) and associated factors of myocardial injury in children on doxorubicin cancer chemotherapy. METHODS: Design: A cross-sectional study. SETTING AND SUBJECTS: A hospital-based study conducted on children aged 1-month to 12.4-years who had a diagnosis of cancer and were admitted at Kenyatta National Hospital (KNH). INTERVENTIONS AND OUTCOMES: The patients underwent Echocardiography (ECHO) before their scheduled chemotherapy infusion. Twenty-four (24) hours after the chemotherapy infusion the patients had an evaluation of the serum cardiac troponin T (cTnT) and a repeat ECHO. Myocardial injury was defined as cTnT level > 0.014 ng/ml or a Fractional Shortening (FS) of < 29% on ECHO. RESULTS: One hundred (100) children were included in the final analysis. Thirty-two percent (32%) of the study population had an elevated cTnT. A cumulative doxorubicin dose of > 175 mg/m2 was significantly associated with and elevated cTnT (OR, 10.76; 95% CI, 1.18-97.92; p = 0.035). Diagnosis of nephroblastoma was also associated with an elevated cTnT (OR, 3.0; 95% CI, 1.23-7.26) but not statistically significant (p = 0.105). Nine percent (9%) of the participants had echocardiographic evidence of myocardial injury. CONCLUSION: When compared to echocardiography, elevated levels of cTnT showed a higher association with early-occurring chemotherapy-induced myocardial injury among children on cancer treatment at a tertiary teaching and referral hospital in Kenya.


Assuntos
Antibióticos Antineoplásicos , Biomarcadores , Cardiotoxicidade , Doxorrubicina , Neoplasias , Centros de Atenção Terciária , Troponina T , Humanos , Estudos Transversais , Masculino , Feminino , Doxorrubicina/efeitos adversos , Criança , Quênia/epidemiologia , Troponina T/sangue , Pré-Escolar , Antibióticos Antineoplásicos/efeitos adversos , Lactente , Neoplasias/tratamento farmacológico , Neoplasias/sangue , Fatores de Risco , Biomarcadores/sangue , Prevalência , Fatores de Tempo , Regulação para Cima , Cardiopatias/induzido quimicamente , Cardiopatias/epidemiologia , Cardiopatias/diagnóstico por imagem , Cardiopatias/diagnóstico , Cardiopatias/sangue , Fatores Etários , Medição de Risco , Ecocardiografia
18.
BMC Cardiovasc Disord ; 24(1): 350, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38987722

RESUMO

BACKGROUND: Antineoplastic medications, including doxorubicin, idarubicin, and epirubicin, have been found to adversely affect the heart due to oxidative stress - mitochondrial dysfunction - ferroptosis (ORMFs), which act as contributing attributes to anthracycline-induced cardiotoxicity. To better understand this phenomenon, the time-resolved measurements of ORMFS genes were analyzed in this study. METHODS: The effect of three anthracycline drugs on ORMFs genes was studied using a human 3D cardiac microtissue cell model. Transcriptome data was collected over 14 days at two doses (therapeutic and toxic). WGCNA identified key module-related genes, and functional enrichment analysis investigated the biological processes quantified by ssGSEA, such as immune cell infiltration and angiogenesis. Biopsies were collected from heart failure patients and control subjects. GSE59672 and GSE2965 were collected for validation. Molecular docking was used to identify anthracyclines's interaction with key genes. RESULTS: The ORMFs genes were screened in vivo or in vitro. Using WGCNA, six co-expressed gene modules were grouped, with MEblue emerging as the most significant module. Eight key genes intersecting the blue module with the dynamic response genes were obtained: CD36, CDH5, CHI3L1, HBA2, HSD11B1, OGN, RPL8, and VWF. Compared with control samples, all key genes except RPL8 were down-regulated in vitro ANT treatment settings, and their expression levels varied over time. According to functional analyses, the key module-related genes were engaged in angiogenesis and the immune system pathways. In all ANT-treated settings, ssGSEA demonstrated a significant down-regulation of angiogenesis score and immune cell activity, including Activated CD4 T cell, Immature B cell, Memory B cell, Natural killer cell, Type 1 T helper cell, and Type 2 T helper cell. Molecular docking revealed that RPL8 and CHI3L1 show significant binding affinity for anthracyclines. CONCLUSION: This study focuses on the dynamic characteristics of ORMFs genes in both human cardiac microtissues and cardiac biopsies from ANT-treated patients. It has been highlighted that ORMFs genes may contribute to immune infiltration and angiogenesis in cases of anthracycline-induced cardiotoxicity. A thorough understanding of these genes could potentially lead to improved diagnosis and treatment of the disease.


Assuntos
Cardiotoxicidade , Ferroptose , Simulação de Acoplamento Molecular , Estresse Oxidativo , Humanos , Estresse Oxidativo/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Mitocôndrias Cardíacas/genética , Redes Reguladoras de Genes , Fatores de Tempo , Transcriptoma , Epirubicina/efeitos adversos , Doxorrubicina , Antibióticos Antineoplásicos/efeitos adversos , Estudos de Casos e Controles , Idarubicina , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Perfilação da Expressão Gênica , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estudos Longitudinais , Antraciclinas/efeitos adversos , Regulação da Expressão Gênica , Transdução de Sinais
19.
Heart Vessels ; 39(2): 105-116, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37973710

RESUMO

BACKGROUND: Cardiac dysfunction due to cardiotoxicity from anthracycline chemotherapy is a leading cause of morbidity and mortality in childhood cancer survivors (CCS), and the cumulative incidence of cardiac events has continued to increase. This study identifies an adequate indicator of cardiac dysfunction during long-term follow-up. PROCEDURE: In total, 116 patients (median age: 15.5 [range: 4.7-40.2] years) with childhood cancer who were treated with anthracycline were divided into three age groups for analysis (C1: 4-12 years of age, C2: 13-18 years of age, C3: 19-40 years of age), and 116 control patients of similar ages were divided into three corresponding groups (N1, N2, and N3). Layer-specific strains were assessed for longitudinal strain (LS) and circumferential strain (CS). The total and segmental intraventricular pressure gradients (IVPG) were also calculated based on Doppler imaging of the mitral inflow using Euler's equation. RESULTS: Conventional echocardiographic parameters were not significantly different between the patients and controls. All layers of the LS and inner and middle layers of the basal and papillary CS in all ages and all IVPGs in C2 and C3 decreased compared to those of corresponding age groups. Interestingly, basal CS and basal IVPG in CCS showed moderate correlation and both tended to rapidly decrease with aging. Furthermore, basal IVPG and anthracycline dose showed significant correlations. CONCLUSIONS: Basal CS and total and basal IVPGs may be particularly useful indicators of cardiotoxicity in long-term follow-up.


Assuntos
Sobreviventes de Câncer , Cardiopatias , Neoplasias , Humanos , Criança , Adolescente , Adulto Jovem , Adulto , Pré-Escolar , Cardiotoxicidade/tratamento farmacológico , Antraciclinas/efeitos adversos , Pressão Ventricular , Seguimentos , Neoplasias/tratamento farmacológico , Neoplasias/complicações , Cardiopatias/diagnóstico , Cardiopatias/diagnóstico por imagem , Antibióticos Antineoplásicos/efeitos adversos
20.
J Appl Toxicol ; 44(10): 1606-1615, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38943348

RESUMO

Doxorubicin-based chemotherapy is a widely used first-line treatment for breast cancer, yet it is associated with various side effects, including splenic atrophy. However, the pathogenic mechanisms underlying doxorubicin-induced atrophy of the spleen remain unclear. This study investigates that doxorubicin treatment leads to splenic atrophy through several interconnected pathways involving histological changes, an inflammatory response, and apoptosis. Immunohistochemical and western blot analyses revealed reduced size of white and red pulp, decreased cellularity, amyloidosis, and fibrotic remodeling in the spleen following doxorubicin treatment. Additionally, increased secretion of pro-inflammatory cytokines was detected using an antibody array and enzyme-linked immunosorbent assay (ELISA), which triggers inflammation through the regulation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kappa B (NF-κB) signaling pathways. Further analysis revealed that the loss of regulators and effectors of the oxidative defense system, including sirtuin (Sirt)3, Sirt5, superoxide dismutase (SOD)1, and SOD2, was implicated in the upstream regulation of caspase-dependent cellular apoptosis. These findings provide insights on the pathogenic mechanisms underlying doxorubicin-induced splenic atrophy and suggest that further investigation may be warranted to explore strategies for managing potential side effects in breast cancer patients treated with doxorubicin.


Assuntos
Atrofia , Neoplasias da Mama , Doxorrubicina , Baço , Doxorrubicina/toxicidade , Animais , Feminino , Baço/efeitos dos fármacos , Baço/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Humanos , Atrofia/induzido quimicamente , Camundongos , Apoptose/efeitos dos fármacos , Antibióticos Antineoplásicos/toxicidade , Antibióticos Antineoplásicos/efeitos adversos , Ensaios Antitumorais Modelo de Xenoenxerto , Transdução de Sinais/efeitos dos fármacos , NF-kappa B/metabolismo , Citocinas/metabolismo , Fator de Transcrição STAT3/metabolismo , Linhagem Celular Tumoral
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