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1.
Lancet Haematol ; 8(11): e818-e827, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34634256

RESUMO

BACKGROUND: Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) is a front-line treatment for patients with aggressive B-cell lymphomas. Bcl-2 is associated with chemoresistance due to BCL2 gene rearrangement or protein overexpression and is antagonised by venetoclax. We aimed to assess the safety of venetoclax with dose-adjusted EPOCH-R as initial therapy in aggressive B-cell lymphoma. METHODS: We conducted a single-arm, phase 1 study across seven treatment centres in the USA. Eligible patients were aged 18-80 years with histologically confirmed, previously untreated diffuse large B-cell lymphoma, transformed indolent non-Hodgkin lymphoma, high-grade B-cell lymphoma with double-hit or not otherwise specified, or primary mediastinal B-cell lymphoma, with Ann Arbor stage II-IV and Eastern Cooperative Oncology Group performance status of 0-2. Participants received six cycles of oral venetoclax 400 mg, 600 mg, or 800 mg once daily for 10 days per cycle with dose-adjusted EPOCH-R (one cycle every 3 weeks; baseline doses were intravenous rituximab 375 mg/m2 on day 1, intravenous etoposide 50 mg/m2 on days 1-4, oral prednisone 60 mg/m2 twice daily on days 1-5, intravenous vincristine 0·4 mg/m2 on days 1-4, intravenous cyclophosphamide 750 mg/m2 on day 5, and intravenous doxorubicin 10 mg/m2 on days 1-4). A subsequent cohort received venetoclax 600 mg once daily for 5 days per cycle. The primary endpoints were the maximum tolerated dose, dose-limiting toxicities, and the recommended phase 2 dose of venetoclax. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov, NCT03036904, and enrolment is now closed. FINDINGS: Between Feb 3, 2017, and June 4, 2019, 34 patients were assessed for eligibility, and 30 were enrolled and received venetoclax with dose-adjusted EPOCH-R. The median patient age was 64·0 years (IQR 51·6-69·4). The maximum tolerated dose was 800 mg for 10 days and the established recommended phase 2 dose was 600 mg for 5 days due to tolerability for treatment duration. One (3%) of 30 patients had a dose-limiting toxicity in cycle one (grade 4 thrombocytopenia with 800 mg dose). The most common grade 3-4 adverse events were cytopenias (28 [93%] of 30 patients); febrile neutropenia occurred in 19 (63%) patients. Grade 3-4 non-haematological adverse events included hypophosphataemia (n=10), hypokalaemia (n=7), and hyperglycaemia (n=5). Serious adverse events included infection (n=7) and gastrointestinal toxicities including abdominal pain (n=3), colonic perforation (n=1), and small intestinal obstruction (n=1). There was one treatment-related death (sepsis). Overall response rate was 96·7% (95% CI 82·8-99·9); 28 (93·3% [77·9-99·2]) of 30 patients had complete response and one (3·3% [0·1-17·2]) had a partial response. INTERPRETATION: Venetoclax with dose-adjusted EPOCH-R showed an acceptable safety profile at the recommended phase 2 dose and had encouraging preliminary activity in this population at high risk of adverse outcomes, and is worthy of further study. The combination is being investigated in Alliance 051701 (NCT03984448). FUNDING: Genentech.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Sulfonamidas/uso terapêutico , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Feminino , Humanos , Linfoma de Células B/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Vincristina/uso terapêutico
2.
Int J Mol Sci ; 22(19)2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34639051

RESUMO

Defects in cardiac contractility and heart failure (HF) are common following doxorubicin (DOX) administration. Different miRs play a role in HF, and their targeting was suggested as a promising therapy. We aimed to target miR-24, a suppressor upstream of junctophilin-2 (JP-2), which is required to affix the sarcoplasmic reticulum to T-tubules, and hence the release of Ca2+ in excitation-contraction coupling using pachymic acid (PA) and/or losartan (LN). HF was induced with DOX (3.5 mg/kg, i.p., six doses, twice weekly) in 24 rats. PA and LN (10 mg/kg, daily) were administered orally for four weeks starting the next day of the last DOX dose. Echocardiography, left ventricle (LV) biochemical and histological assessment and electron microscopy were conducted. DOX increased serum BNP, HW/TL, HW/BW, mitochondrial number/size and LV expression of miR-24 but decreased EF, cardiomyocyte fiber diameter, LV content of JP-2 and ryanodine receptors-2 (RyR2). Treatment with either PA or LN reversed these changes. Combined PA + LN attained better results than monotherapies. In conclusion, HF progression following DOX administration can be prevented or even delayed by targeting miR-24 and its downstream JP-2. Our results, therefore, suggest the possibility of using PA alone or as an adjuvant therapy with LN to attain better management of HF patients, especially those who developed tolerance toward LN.


Assuntos
Doxorrubicina/efeitos adversos , Regulação da Expressão Gênica , Insuficiência Cardíaca/etiologia , Proteínas de Membrana/genética , MicroRNAs/genética , Triterpenos/farmacologia , Animais , Cardiomegalia/diagnóstico , Cardiomegalia/tratamento farmacológico , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Testes de Função Cardíaca , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/ultraestrutura , Ratos , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Transdução de Sinais
3.
Nutrients ; 13(10)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34684434

RESUMO

Despite the progress in the development of new anticancer strategies, cancer is rapidly spreading around the world and remains one of the most common diseases. For more than 40 years, doxorubicin has been widely used in the treatment of solid and hematological tumors. At the same time, the problem of its cardiotoxicity remains unresolved, despite the high efficiency of this drug. Symptomatic therapy is used as a treatment for side-effects of doxorubicin or pathological conditions that have already appeared in their background. To date, there are no treatment methods for doxorubicin cardiomyopathy as such. A drug such as nicotinamide riboside can play an important role in solving this problem. Nicotinamide riboside is a pyridine nucleoside similar to vitamin B3 that acts as a precursor to NAD+. There is no published research on nicotinamide riboside effects on cardiomyopathy, despite the abundance of works devoted to the mechanisms of its effects in various pathologies. The review analyzes information about the effects of nicotinamide riboside on various experimental models of pathologies, its role in the synthesis of NAD+, and also considers the possibility and prospects of its use for the prevention of doxorubicin cardiomyopathy.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/etiologia , Cardiotônicos/uso terapêutico , Doxorrubicina/efeitos adversos , Niacinamida/análogos & derivados , Compostos de Piridínio/uso terapêutico , Animais , Biomarcadores , Cardiomiopatias/metabolismo , Cardiomiopatias/prevenção & controle , Cardiotônicos/farmacologia , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Gerenciamento Clínico , Modelos Animais de Doenças , Suscetibilidade a Doenças , Humanos , Redes e Vias Metabólicas , NAD/biossíntese , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Compostos de Piridínio/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirtuínas/metabolismo
4.
Nutrients ; 13(9)2021 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-34579145

RESUMO

Short-term calorie reduction (SCR) requires individuals to reduce their calorie intake to less than 50% of normal requirements and has shown good tolerance and potential benefits in prior studies addressing gynecological cancer patients. More studies are needed to further confirm its safety, feasibility, and effects in patients with different cancers, including hematological malignancies. This pilot cohort study with a matched-pair comparison group was registered at ClinicalTrails.gov [201810112RIND]. Adult patients diagnosed with advanced-stage diffuse large-B cell lymphoma were recruited (SCR group) and matched with one comparison patient (comparison group), each in a manner blinded to their outcomes. The SCR group undertook at least two cycles of 48 h water fast along with their chemotherapy R-CHOP. Descriptive analysis and generalized estimating equations were used to analyze the data. Six participants completed multiple cycles of SCR and were compared to their six counterparts in the comparison group. The results showed that SCR is safe and feasible in terms of a high compliance rate and stable nutritional status. The SCR was associated with benefits in post-chemotherapy hematological parameters (i.e., erythrocyte [p < 0.001] and lymphocyte counts [p < 0.001]). More randomized controlled trials are needed to validate the effects of SCR on different types of cancer populations.


Assuntos
Restrição Calórica/métodos , Quimioterapia de Indução/métodos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Restrição Calórica/efeitos adversos , Terapia Combinada , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Estudos de Viabilidade , Feminino , Humanos , Linfoma Difuso de Grandes Células B/dietoterapia , Masculino , Análise por Pareamento , Pessoa de Meia-Idade , Projetos Piloto , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Rituximab/uso terapêutico , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Vincristina/uso terapêutico
5.
Int J Clin Oncol ; 26(12): 2275-2281, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34468885

RESUMO

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and aggressive disease that is often diagnosed at an advanced stage. There is no standard treatment for metastatic ACC; EDP-M (etoposide, doxorubicin, and cisplatin plus mitotane) is one treatment option. A randomized controlled trial (FIRM-ACT) evaluating the efficacy of EDP-M showed progression-free survival (PFS) was 5.0 months, overall survival (OS) was 14.8 months, the response rate was 19%, and adrenal insufficiency occurred in 3.4% of patients. However, the efficacy and safety of this regimen in Asia are not fully reported. METHODS: We retrospectively analyzed 43 patients diagnosed with metastatic ACC at the National Cancer Center Hospital between 1997 and 2020. We evaluated PFS, OS, and response in 17 patients who received EDP-M as first-line therapy. RESULTS: The median age at treatment initiation was 45 years (range 18-74). Eight patients (47%) had autonomous hormone production, including six patients with hypercortisolism. The best response of partial response and stable disease was seen in two (12%) and ten (59%) patients, respectively. The median PFS was 6.2 months [95% confidence interval (CI): 4.3-10.0]. The median OS was 15.4 months (95% CI 11.6-not reached). Three patients received only one cycle due to adverse effects associated with hypercortisolism. Grade 3/4 adverse events associated with adrenal insufficiency occurred in three (17%) cases, resulting in EDP-M discontinuation. CONCLUSIONS: The EDP-M regimen had similar PFS to that observed in FIRM-ACT. Adrenal insufficiency was more frequent in the current study, but this could be managed with supportive endocrinological care such as cortisol replacement.


Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Adolescente , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/efeitos adversos , Doxorrubicina/efeitos adversos , Etoposídeo/efeitos adversos , Humanos , Pessoa de Meia-Idade , Mitotano/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
6.
Int J Mol Sci ; 22(16)2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34445179

RESUMO

The aim of the present study was to perform kidney messenger ribonucleic acid (mRNA) analysis in normotensive, Hannover Sprague-Dawley (HanSD) rats and hypertensive, Ren-2 renin transgenic rats (TGR) after doxorubicin-induced heart failure (HF) with specific focus on genes that are implicated in the pathophysiology of HF-associated cardiorenal syndrome. We found that in both strains renin and angiotensin-converting enzyme mRNA expressions were upregulated indicating that the vasoconstrictor axis of the renin-angiotensin system was activated. We found that pre-proendothelin-1, endothelin-converting enzyme type 1 and endothelin type A receptor mRNA expressions were upregulated in HanSD rats, but not in TGR, suggesting the activation of endothelin system in HanSD rats, but not in TGR. We found that mRNA expression of cytochrome P-450 subfamily 2C23 was downregulated in TGR and not in HanSD rats, suggesting the deficiency in the intrarenal cytochrome P450-dependent pathway of arachidonic acid metabolism in TGR. These results should be the basis for future studies evaluating the pathophysiology of cardiorenal syndrome secondary to chemotherapy-induced HF in order to potentially develop new therapeutic approaches.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Doxorrubicina/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Hipertensão/genética , Nefropatias/induzido quimicamente , Rim/efeitos dos fármacos , Renina/genética , Animais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Hipertensão/complicações , Hipertensão/fisiopatologia , Rim/fisiopatologia , Nefropatias/genética , Nefropatias/fisiopatologia , Masculino , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Sistema Renina-Angiotensina/efeitos dos fármacos
7.
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
8.
Life Sci ; 284: 119879, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34390723

RESUMO

AIMS: Doxorubicin (DOX) is an important drug for the treatment of various tumor entities. However, the occurrence of heart failure limits its application. This study investigated differential gene expression profiles in the left and right ventricles of DOX treated mice with either preserved or impaired myocardial function. We provide new mechanistic insights into the pathophysiology of DOX-induced heart failure and have discovered pathways that counteract DOX-induced cardiotoxicity. MAIN METHODS: We used in total 48 male mice and applied a chronic low dose DOX administration (5 mg/kg per injection, in total 20 mg/kg over 4 weeks) to induce heart failure. Echocardiographic parameters were evaluated one week after the final dose and mice were separated according to functional parameters into doxorubicin responding and non-responding animals. Post mortem, measurements of reactive oxygen species (ROS) and gene expression profiling was performed in separated right and left hearts. KEY FINDINGS: We detected significant ROS production in the left heart of the mice in response to DOX treatment, although interestingly, not in the right heart. We found that transcriptional changes differ between right and left heart correlating with the occurrence of myocardial dysfunction. SIGNIFICANCE: Doxorubicin induces changes in gene expression in the entire heart of animals without necessarily impairing cardiac function. We identified a set of transcripts that are associated with DOX cardiotoxicity. These might represent promising targets to ameliorate DOX-induced heart failure. Moreover, our results emphasize that parameters of left and right heart function should be evaluated during standardized echocardiography in patients undergoing DOX therapy.


Assuntos
Doxorrubicina/efeitos adversos , Testes de Função Cardíaca , Miocárdio/patologia , Transcrição Genética , Animais , Análise por Conglomerados , Eletrocardiografia , Perfilação da Expressão Gênica , Testes de Função Cardíaca/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos
9.
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
10.
Dokl Biochem Biophys ; 499(1): 273-281, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34426926

RESUMO

BACKGROUND: Chemotherapy drugs commonly used for cancer therapy, but chemotherapy has limitation due to side effects. Current studies suggest natural products are reducing the side effects of chemotherapy medicines. In this study, we examined the side effects of doxorubicin (Dox) in esophageal cancer cells (CSCs) derived tumors in vivo. METHODS: Esophageal cancer cells (YMI) were treated in vitro with daphnetin (DAP) along with DOX. The MTT assay was used for estimating the cell viability and Annexin/7-AAD was used for the determination of apoptosis. Cell cycle arrest was conducted using the PI-staining method. The potential effect of DAP was evaluated by the estimation of oxidative stress such as total antioxidant capacity (TAC), malondialdehyde (MDA) and superoxide dismutase (SOD) and body weight in the xenograft mice. RESULTS: DAP can protect Dox cell toxicity by suppressing cell apoptosis of ESCC. DAP arrest the cells as S-phase. In vivo experimental study showed that Dox simultaneously with DAP decreases the tumor size along with increased body weight in the nude mice compared to Dox alone treated group mice. Dox along with the DAP exhibited less systemic toxicity and reduced oxidative stress fraction circulation. CONCLUSION: The result suggests that daphnetin may be used as an adjuvant therapy to reduce the systemic toxicity of chemotherapeutic agents, such as DOX, in stem cell treatment with ESCC cancer.


Assuntos
Antineoplásicos/efeitos adversos , Doxorrubicina/efeitos adversos , Neoplasias Esofágicas/patologia , Células-Tronco Neoplásicas/patologia , Umbeliferonas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos
11.
Medicine (Baltimore) ; 100(34): e26690, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34449454

RESUMO

BACKGROUND: It is well known that liposome-based delivery of cytotoxic chemotherapeutics has been proposed as a putative strategy to enhance drug tolerability and efficacy compared to the conventional chemotherapy. However, its potential effect on improving prognosis remains largely unknown. The current meta-analysis is to explore the prognosis of cancer patients undergoing liposomal doxorubicin-based chemotherapy. METHODS: A detailed review of English and Chinese literature was conducted up to March 21, 2020. We evaluate its possible correlations using hazard ratios (HRs) with 95% confidence intervals (CIs). The pooled data were calculated by STATA software and Review Manager 5.3 software. RESULTS: Consequently, 26 studies including 7943 patients were satisfied in current analysis. There were no significant differences between liposomal and conventional chemotherapy in OS (HR = 0.98, 95%CI: 0.93-1.04, P = .544) and PFS (HR = 1.00, 95%CI: 0.92-1.10, P = .945). Likewise, subgroup-analysis regarding country, cancer type, and sample sizes also showed the similar results of the 2 paired groups. CONCLUSION: Taken together, our finding has demonstrated that there was no association of undergoing liposomal doxorubicin-based chemotherapy with cancer prognosis. However, detailed and further studies are needed to confirm our conclusion.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doxorrubicina/análogos & derivados , Neoplasias/tratamento farmacológico , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Humanos , Estudos Multicêntricos como Assunto , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/uso terapêutico , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281156

RESUMO

Cardiotoxicity is associated with the long-term clinical application of doxorubicin (DOX) in cancer patients. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) including exosomes have been suggested for the treatment of various diseases, including ischemic diseases. However, the effects and functional mechanism of MSC-sEVs in DOX-induced cardiomyopathy have not been clarified. Here, MSC-sEVs were isolated from murine embryonic mesenchymal progenitor cell (C3H/10T1/2) culture media, using ultrafiltration. H9c2 cardiac myoblast cells were pretreated with MSC-sEVs and then exposed to DOX. For in vivo studies, male C57BL/6 mice were administered MSC-sEVs intravenously, prior to a single dose of DOX (15 mg/kg, intraperitoneal). The mice were sacrificed 14 days after DOX treatment. The results showed that MSC-sEVs protected cardiomyocytes from DOX-induced cell death. H9c2 cells treated with DOX showed downregulation of both phosphorylated Akt and survivin, whereas the treatment of MSC-sEVs recovered expression, indicating their anti-apoptotic effects. Three microRNAs (miRNAs) (miR 199a-3p, miR 424-5p, and miR 21-5p) in MSC-sEVs regulated the Akt-Sp1/p53 signaling pathway in cardiomyocytes. Among them, miR 199a-3p was involved in regulating survivin expression, which correlated with the anti-apoptotic effects of MSC-sEVs. In in vivo studies, the echocardiographic results showed that the group treated with MSC-sEVs recovered from DOX-induced cardiomyopathy, showing improvement of both the left ventricle fraction and ejection fraction. MSC-sEVs treatment also increased both survivin and B-cell lymphoma 2 expression in heart tissue compared to the DOX group. Our results demonstrate that MSC-sEVs have protective effects against DOX-induced cardiomyopathy by upregulating survivin expression, which is mediated by the regulation of Akt activation by miRNAs in MSC-sEVs. Thus, MSC-sEVs may be a novel therapy for the prevention of DOX-induced cardiomyopathy.


Assuntos
Cardiomiopatias/metabolismo , Vesículas Extracelulares/metabolismo , Células-Tronco Mesenquimais/metabolismo , Animais , Apoptose/efeitos dos fármacos , Cardiomiopatias/prevenção & controle , Cardiotoxicidade/metabolismo , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Exossomos/metabolismo , Vesículas Extracelulares/fisiologia , Masculino , Células-Tronco Mesenquimais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo , Survivina/genética , Survivina/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
13.
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
14.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207549

RESUMO

Doxorubicin (DOX) is a widely used anticancer drug. However, its clinical use is severely limited due to drug-induced cumulative cardiotoxicity, which leads to progressive cardiomyocyte dysfunction and heart failure. Enormous efforts have been made to identify potential strategies to alleviate DOX-induced cardiotoxicity; however, to date, no universal and highly effective therapy has been introduced. Here we reported that cinnamic acid (CA) derivatives exert a multitarget protective effect against DOX-induced cardiotoxicity. The experiments were performed on rat cardiomyocytes (H9c2) and human induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) as a well-established model for cardiac toxicity assessment. CA derivatives protected cardiomyocytes by ameliorating DOX-induced oxidative stress and viability reduction. Our data indicated that they attenuated the chemotherapeutic's toxicity by downregulating levels of caspase-3 and -7. Pre-incubation of cardiomyocytes with CA derivatives prevented DOX-induced motility inhibition in a wound-healing assay and limited cytoskeleton rearrangement. Detailed safety analyses-including hepatotoxicity, mutagenic potential, and interaction with the hERG channel-were performed for the most promising compounds. We concluded that CA derivatives show a multidirectional protective effect against DOX-induced cardiotoxicity. The results should encourage further research to elucidate the exact molecular mechanism of the compounds' activity. The lead structure of the analyzed CA derivatives may serve as a starting point for the development of novel therapeutics to support patients undergoing DOX therapy.


Assuntos
Cardiotônicos/farmacologia , Cardiotoxicidade , Cinamatos/farmacologia , Doxorrubicina/efeitos adversos , Miócitos Cardíacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Doxorrubicina/farmacologia , Células Hep G2 , Humanos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos
15.
Nutrients ; 13(7)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201904

RESUMO

Doxorubicin is an anthracycline that is commonly used as a chemotherapy drug due to its cytotoxic effects. The clinical use of doxorubicin is limited due to its known cardiotoxic effects. Treatment with anthracyclines causes heart failure in 15-17% of patients, resulting in mitochondrial dysfunction, the accumulation of reactive oxygen species, intracellular calcium dysregulation, the deterioration of the cardiomyocyte structure, and apoptotic cell death. Polyphenols have a wide range of beneficial properties, and particular importance is given to Bergamot Polyphenolic Fraction; Oleuropein, one of the main polyphenolic compounds of olive oil; and Cynara cardunculus extract. These natural compounds have particular beneficial characteristics, owing to their high polyphenol contents. Among these, their antioxidant and antoproliferative properties are the most important. The aim of this paper was to investigate the effects of these three plant derivatives using an in vitro model of cardiotoxicity induced by the treatment of rat embryonic cardiomyoblasts (H9c2) with doxorubicin. The biological mechanisms involved and the crosstalk existing between the mitochondria and the endoplasmic reticulum were examined. Bergamot Polyphenolic Fraction, Oleuropein, and Cynara cardunculus extract were able to decrease the damage induced by exposure to doxorubicin. In particular, these natural compounds were found to reduce cell mortality and oxidative damage, increase the lipid content, and decrease the concentration of calcium ions that escaped from the endoplasmic reticulum. In addition, the direct involvement of this cellular organelle was demonstrated by silencing the ATF6 arm of the Unfolded Protein Response, which was activated after treatment with doxorubicin.


Assuntos
Cardiotoxicidade/tratamento farmacológico , Cynara/química , Doxorrubicina/efeitos adversos , Olea/química , Extratos Vegetais/farmacologia , Animais , Antraciclinas , Anti-Infecciosos/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Suplementos Nutricionais , Glucosídeos Iridoides , Mitocôndrias , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo , Polifenóis/farmacologia , Ratos , Espécies Reativas de Oxigênio/metabolismo
16.
Nihon Yakurigaku Zasshi ; 156(4): 214-219, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34193698

RESUMO

Although the cardiotoxicity of anti-cancer drugs is an important issue, the underlying mechanisms remain unknown. To develop a sensitive assay system for cardiotoxicity, we examined effects of anticancer drugs on contractile functions of human iPS cell-derived cardiomyocytes by using non-invasive motion field imaging analysis with extended drug exposure time. We succeeded in continuously measuring stable contractile function. The continued exposure revealed that the difference in cardiotoxicity between cardiotoxic doxorubicin and less toxic erlotinib was more evident after 8 days of treatment than with 3 days of treatment, suggesting that continued exposure improved the predictive power for cardiotoxicity of anti-cancer drugs.


Assuntos
Células-Tronco Pluripotentes Induzidas , Miócitos Cardíacos , Cardiotoxicidade , Células Cultivadas , Doxorrubicina/efeitos adversos , Humanos
17.
J Biochem Mol Toxicol ; 35(9): e22859, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34328254

RESUMO

Clinically, the use of doxorubicin (DOX) is limited due to DOX-induced cardiotoxicity (DIC). The current study aimed to evaluate the cardioprotective effect of trehalose (TRE) against DIC in a female Swiss albino mouse model. Mice were divided into five experimental groups: Gp. I: saline control group (200 µl/mouse saline three times per week for 3 weeks day after day), Gp. II: DOX-treated group (2 mg/kg body weight three times per week for 3 weeks day after day), Gp. III: TRE group (200 µg/mouse three times per week for 3 weeks day after day), Gp. IV: DOX + TRE cotreatment group (animals were coadministered with DOX and TRE as in Gp. II and III, respectively), and Gp. V: DOX + TRE posttreatment group (animals were treated with DOX as in Gp. II followed by treatment with TRE as in Gp. III). DOX-treated mice showed significant elevation in cardiac injury biomarkers (lactate dehydrogenase, creatine kinase isoenzyme-MB, and cardiac troponin I), cardiac oxidative stress (OS) markers (malondialdehyde and myeloperoxidase), and cardiac levels of autophagy-related protein 5. Moreover, DOX significantly reduced the levels of total antioxidant capacity and activities of catalase and glutathione S-transferase. In contrast, TRE treatment of DOX-administered mice significantly improved almost all of the above-mentioned assessed parameters. Furthermore, histopathological changes of cardiac tissues observed in mice treated with TRE in combination with DOX were significantly improved as compared to DOX-treated animals. Taken together, the present study provides evidence that TRE has cardioprotective effects against DIC, which is likely mediated via suppression of OS and autophagy.


Assuntos
Autofagia/efeitos dos fármacos , Cardiotônicos/farmacologia , Cardiotoxicidade/tratamento farmacológico , Doxorrubicina/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Trealose/farmacologia , Animais , Biomarcadores/metabolismo , Cardiotoxicidade/metabolismo , Doxorrubicina/farmacologia , Feminino , Camundongos , Miocárdio/metabolismo
18.
Korean J Intern Med ; 36(5): 1181-1189, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34265889

RESUMO

BACKGROUND/AIMS: Febrile neutropenia (FN) interferes with the proper chemotherapy dose density or intensity in non-Hodgkin's lymphoma (NHL) patients. Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) ± rituximab has an intermediate FN risk. Prophylactic granulocyte colony-stimulating factor (G-CSF) support is recommended for patients with other host-related risk factors. METHODS: We evaluated the risk factors for FN-related admission in NHL patients who have received primary G-CSF (lenograstim) prophylaxis. RESULTS: Data from 148 patients were analyzed. The incidence of neutropenic fever was 96 events (12.2%), and the median period was 3.85 days (range, 0 to 5.9); the median duration of neutropenia was 4.21 days (range, 3.3 to 5.07). Eighty-three FN-related admissions were reported. Advanced age (> 60 years), female sex, a low albumin level, and prednisone use were associated with FN-related admission in multivariable analysis (p = 0.010, p < 0.001, and p = 0.010, respectively). A comparison between diffuse large B-cell lymphoma patients treated with R-CHOP and pegylated G-CSF and those treated with R-CHOP and lenograstim did not reveal significant differences in the FN-related admission rate between the two groups, although the lenograstim-treated group had a higher incidence of severe neutropenia. CONCLUSION: Elderly patients, female patients, and patients with low albumin levels need to be actively followed-up for FN even when primary prophylaxis with G-CSF has been used.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma não Hodgkin , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/efeitos adversos , Doxorrubicina/efeitos adversos , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Pessoa de Meia-Idade , Prednisona/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Vincristina/efeitos adversos
19.
Biomed Res Int ; 2021: 8569921, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34327238

RESUMO

Doxorubicin is a cornerstone chemotherapeutic drug widely used to treat various cancers; its dose-dependent cardiomyopathy, however, is one of the leading causes of treatment-associated mortality in cancer survivors. Patients' threshold doses leading to doxorubicin-induced cardiomyopathy (DIC) and heart failure are highly variable, mostly due to genetic variations in individuals' genomes. However, genetic susceptibility to DIC remains largely unidentified. Here, we combined a genetic approach in the zebrafish (Danio rerio) animal model with a genome-wide association study (GWAS) in humans to identify genetic susceptibility to DIC and heart failure. We firstly reported the cardiac and skeletal muscle-specific expression and sarcomeric localization of the microtubule-associated protein 7 domain-containing protein 1b (Map7d1b) in zebrafish, followed by expression validation in mice. We then revealed that disruption of the map7d1b gene function exaggerated DIC effects in adult zebrafish. Mechanistically, the exacerbated DIC are likely conveyed by impaired autophagic degradation and elevated protein aggregation. Lastly, we identified 2 MAP7D1 gene variants associated with cardiac functional decline and heart failure in cancer patients who received doxorubicin therapy. Together, this study identifies MAP7D1 as a clinically relevant susceptibility gene to DIC and heart failure, providing useful information to stratify cancer patients with a high risk of incurring severe cardiomyopathy and heart failure after receiving chemotherapy.


Assuntos
Cardiomiopatias/induzido quimicamente , Cardiomiopatias/genética , Doxorrubicina/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Animais , Apoptose , Autofagia , Elementos de DNA Transponíveis/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Insuficiência Cardíaca/fisiopatologia , Modelos Biológicos , Músculo Esquelético/metabolismo , Mutação/genética , Miocárdio/metabolismo , Miócitos Cardíacos/patologia , Polimorfismo de Nucleotídeo Único/genética , Agregados Proteicos , Fatores de Risco , Estresse Fisiológico
20.
Sci Rep ; 11(1): 13866, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230586

RESUMO

Human induced pluripotent stem (iPS) cell technologies coupled with genetic engineering now facilitate the study of the molecular underpinnings of disease in relevant human cell types. Application of CRISPR/Cas9-based approaches for genome-scale functional screening in iPS-derived cells, however, has been limited by technical constraints, including inefficient transduction in pooled format, loss of library representation, and poor cellular differentiation. Herein, we present optimized approaches for whole-genome CRISPR/Cas9 based screening in human iPS derived cardiomyocytes with near genome-wide representation at both the iPS and differentiated cell stages. As proof-of-concept, we perform a screen to investigate mechanisms underlying doxorubicin mediated cell death in iPS derived cardiomyocytes. We identified two poorly characterized, human-specific transporters (SLCO1A2, SLCO1B3) whose loss of function protects against doxorubicin-cardiotoxicity, but does not affect cell death in cancer cells. This study provides a technical framework for genome-wide functional screening in iPS derived cells and identifies new targets to mitigate doxorubicin-cardiotoxicity in humans.


Assuntos
Sistemas CRISPR-Cas/genética , Cardiotoxicidade/patologia , Doxorrubicina/efeitos adversos , Genoma Humano , Células-Tronco Pluripotentes Induzidas/metabolismo , Miócitos Cardíacos/metabolismo , Linhagem Celular Tumoral , Humanos , Lentivirus/metabolismo , Fenótipo , RNA Guia/genética
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