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1.
Life Sci ; 241: 117173, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31843530

RESUMO

PURPOSE: Doxorubicin, as an effective chemotherapeutic drug, is commonly used for combating various solid and hematological tumors. However, doxorubicin-induced cardiotoxicity is considered as a serious adverse effect, and it limits the clinical use of this chemotherapeutic drug. The use of melatonin can lead to a decrease in the cardiotoxic effect induced by doxorubicin. The aim of this review was to evaluate the potential role of melatonin in the prevention of doxorubicin-induced cardiotoxicity. METHODS: This review was conducted by a full systematic search strategy based on PRISMA guidelines for the identification of relevant literature in the electronic databases of PubMed, Web of Science, Embase, and Scopus up to January 2019 using search terms in the titles and abstracts. 286 articles were screened in accordance with our inclusion and exclusion criteria. Finally, 28 articles were selected in this systematic review. RESULTS: The findings demonstrated that doxorubicin-treated groups had increased mortality, decreased body weight and heart weight, and increased ascites compared to the control groups; the co-administration of melatonin revealed an opposite pattern compared to the doxorubicin-treated groups. Also, this chemotherapeutic agent can lead to biochemical and histopathological changes; as for most of the cases, these alterations were reversed near to normal levels (control groups) by melatonin co-administration. Melatonin exerts these protection effects through mechanisms of anti-oxidant, anti-apoptosis, anti-inflammatory, and mitochondrial function. CONCLUSION: The results of this systematic review indicated that co-administration of melatonin ameliorates the doxorubicin-induced cardiotoxicity.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Antioxidantes/uso terapêutico , Cardiotoxicidade/prevenção & controle , Doxorrubicina/efeitos adversos , Melatonina/uso terapêutico , Neoplasias/tratamento farmacológico , Cardiotoxicidade/etiologia , Humanos , Neoplasias/patologia , Prognóstico
2.
BMC Complement Altern Med ; 19(1): 360, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31829159

RESUMO

BACKGROUND: Lingguizhugan decoction (LGZG), an ancient Chinese herbal formula, has been used to treat cardiovascular diseases in eastern Asia. We investigated whether LGZG has protective activity and the mechanism underlying its effect in an animal model of heart failure (HF). METHODS: A rat model of HF was established by administering eight intraperitoneal injections of doxorubicin (DOX) (cumulative dose of 16 mg/kg) over a 4-week period. Subsequently, LGZG at 5, 10, and 15 mL/kg/d was administered to the rats intragastrically once daily for 4 weeks. The body weight, heart weight index (HWI), heart weight/tibia length ratio (HW/TL), and serum BNP level were investigated to assess the effect of LGZG on HF. Echocardiography was performed to investigate cardiac function, and H&E staining to visualize myocardial morphology. Myocardial ultrastructure and T-tubule-sarcoplasmic reticulum (TT-SR) junctions were observed by transmission electron microscopy. The JP-2 protein level was determined by Western blotting. The mRNA level of CACNA1S and RyR2 and the microRNA-24 (miR-24) level were assayed by quantitative RT-PCR. RESULTS: Four weeks after DOX treatment, rats developed cardiac damage and exhibited a significantly increased BNP level compared with the control rats (169.6 ± 29.6 pg/mL versus 80.1 ± 9.8 pg/mL, P < 0.001). Conversely, LGZG, especially at the highest dose, markedly reduced the BNP level (93.8 ± 17.9 pg/mL, P < 0.001). Rats treated with DOX developed cardiac dysfunction, characterized by a strong decrease in left ventricular ejection fraction compared with the control (58.5 ± 8.7% versus 88.7 ± 4.0%; P < 0.001). Digoxin and LGZG improved cardiac dysfunction (79.6 ± 6.1%, 69.2 ± 2.5%, respectively) and preserved the left ventricular ejection fraction (77.9 ± 5.1, and 80.5 ± 4.9, respectively, P < 0.01). LGZG also improved the LVEDD, LVESD, and FS and eliminated ventricular hypertrophy, as indicated by decreased HWI and HW/TL ratio. LGZG attenuated morphological abnormalities and mitochondrial damage in the myocardium. In addition, a high dose of LGZG significantly downregulated the expression of miR-24 compared with that in DOX-treated rats (fold change 1.4 versus 3.4, P < 0.001), but upregulated the expression of JP-2 and antagonized DOX-induced T-tubule TT-SR microstructural remodeling. These activities improved periodic Ca2+ transients and cell contraction, which may underly the beneficial effect of LGZG on HF. CONCLUSIONS: LGZG exerted beneficial effects on DOX-induced HF in rats, which were mediated in part by improved TT-SR microstructural remodeling.


Assuntos
Cardiotônicos/farmacologia , Doxorrubicina/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Extratos Vegetais/farmacologia , Retículo Sarcoplasmático/efeitos dos fármacos , Animais , Coração/efeitos dos fármacos , Masculino , Proteínas de Membrana/metabolismo , MicroRNAs , Proteínas Musculares/metabolismo , Miocárdio/química , Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley , Retículo Sarcoplasmático/ultraestrutura
3.
Medicine (Baltimore) ; 98(50): e18249, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852092

RESUMO

RATIONALE: Cancer and chemotherapy individually confer hypercoagulability and increased risks of thrombosis. Most thromboembolic complication after breast cancer chemotherapy was venous thrombosis after multiagent chemotherapy. Arterial thrombosis is extremely rare in early breast cancer patients receiving adjuvant chemotherapy. PRESENTING CONCERNS: A 55-year-old woman with right breast cancer presented to the emergency department with sudden pain, numbness, and swelling in her left hand. She underwent breast conserving surgery and sentinel lymph node biopsy 2 months before the visit. She received the second cycle of adjuvant Adriamycin-cyclophosphamide chemotherapy 5 days before. INTERVENTIONS: Computed tomography angiography revealed acute arterial thrombosis in the left brachial, radial, and ulnar arteries. Unfractionated heparin was initiated immediately, followed by brachial and radial-ulnar thrombectomy, restoring perfusion to the extremity. The postoperative course was uncomplicated; she was discharged on warfarin at a daily dose of 4 mg. OUTCOMES: Chemotherapy was discontinued. Anticoagulation with warfarin was continued. She subsequently received adjuvant endocrine therapy with an aromatase inhibitor and adjuvant radiotherapy. MAIN LESSONS: Despite the low risks of arterial thrombosis in breast cancer, it is a devastating complication with significant morbidity and mortality. Thromboprophylaxis should be considered in those at risk. Immediate anticoagulant therapy and surgical intervention should be considered in affected cases.


Assuntos
Artéria Braquial , Neoplasias da Mama/tratamento farmacológico , Ciclofosfamida/efeitos adversos , Doxorrubicina/efeitos adversos , Artéria Radial , Trombose/induzido quimicamente , Artéria Ulnar , Doença Aguda , Neoplasias da Mama/diagnóstico , Quimioterapia Adjuvante/efeitos adversos , Angiografia por Tomografia Computadorizada , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Quimioterapia Combinada/efeitos adversos , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Trombectomia/métodos , Trombose/diagnóstico , Trombose/cirurgia , Ultrassonografia Doppler
4.
BMC Infect Dis ; 19(1): 848, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615436

RESUMO

BACKGROUND: Pegylated liposomal doxorubicin plays an important role in the treatment of patients with severe refractory human immunodeficiency virus (HIV)-associated Kaposi sarcoma (KS). High cumulative doses of conventional doxorubicin exceeding 500 mg/m2 are known to cause cardiac toxicity. However, the safe cumulative dose of pegylated liposomal doxorubicin is unclear. CASE PRESENTATION: A 40-year-old Japanese man with HIV infection presented with pain, edema, and multiple skin nodules on both legs which worsened over several months. He was diagnosed with HIV-associated KS. He received long-term pegylated liposomal doxorubicin combined with antiretroviral therapy for advanced, progressive KS. The cumulative dose of pegylated liposomal doxorubicin reached 980 mg/m2. The patient's left ventricular ejection fraction remained unchanged from baseline during treatment. After he died as a result of cachexia and wasting, caused by recurrent sepsis and advanced KS, an autopsy specimen of his heart revealed little or no evidence of histological cardiac damage. We also conducted a literature review focusing on histological changes of the myocardium in patients treated with a cumulative dose of pegylated liposomal doxorubicin exceeding 500 mg/m2. CONCLUSIONS: This case report and literature review suggest that high (> 500 mg/m2) cumulative doses of pegylated liposomal doxorubicin may be used without significant histological/clinical cardiac toxicity in patients with HIV-associated KS.


Assuntos
Doxorrubicina/análogos & derivados , Infecções por HIV/patologia , Sarcoma de Kaposi/tratamento farmacológico , Adulto , Antirretrovirais/uso terapêutico , Relação Dose-Resposta a Droga , Doxorrubicina/efeitos adversos , Doxorrubicina/química , Doxorrubicina/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Coração/diagnóstico por imagem , Humanos , Masculino , Miocárdio/patologia , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/química , Polietilenoglicóis/uso terapêutico , Sarcoma de Kaposi/diagnóstico , Sarcoma de Kaposi/etiologia
5.
Gynecol Oncol ; 155(2): 301-304, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31575390

RESUMO

OBJECTIVE: Pegylated liposomal doxorubicin (PLD) has similar reported clinical efficacy compared with conventional doxorubicin with less cardiotoxicity. The manufacturer of PLD advises that cardiac function should be evaluated with endomyocardial biopsy, echocardiography or multigated radionucleotide scan (MUGA) pre-treatment and during therapy. This study was designed to assess the necessity of pre-treatment cardiac evaluation in patients receiving PLD. METHODS: After IRB approval, a retrospective study of all women with gynecologic cancer who received PLD from 2006 to 2018 was performed. Demographic information, treatment records, cardiac risk factors, and cardiac surveillance testing were examined. Wilcoxon signed rank sum test and logistic regression were used to evaluate the association of cumulative PLD exposure with cardiotoxicity. RESULTS: A total of 235 patients received PLD for gynecologic cancer. Patients received a median of 3 cycles of PLD with a cumulative dosage of 237 mg over a median follow-up time of 24 months. Sixteen patients in the cohort (7%) had no cardiac surveillance at all. Of the remaining patients who underwent cardiac testing, 183 (84%) received MUGA scans and 36 (16%) had echocardiography. Of the 56 patients who had both pre- and post-treatment cardiac testing, there was no significant difference in median ejection fraction (p = 0.17). Three patients developed PLD-associated cardiac toxicity but only one patient had severe manifestations requiring discontinuation of PLD therapy. CONCLUSIONS: Routine cardiac testing before, during or after treatment with PLD may be unnecessary. Cardiac testing may be more appropriate for individual patients for whom the clinical suspicion of PLD-related cardiac toxicity is high.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/análogos & derivados , Neoplasias dos Genitais Femininos/tratamento farmacológico , Cardiopatias/induzido quimicamente , Doxorrubicina/efeitos adversos , Substituição de Medicamentos , Ecocardiografia/métodos , Feminino , Cardiopatias/fisiopatologia , Cardiopatias/prevenção & controle , Humanos , Pessoa de Meia-Idade , Imagem Multimodal/métodos , Polietilenoglicóis/efeitos adversos , Angiografia Cintilográfica/métodos , Estudos Retrospectivos , Volume Sistólico/efeitos dos fármacos
6.
Anticancer Res ; 39(10): 5703-5707, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570470

RESUMO

BACKGROUND/AIM: Anthracyclines, such as doxorubicin, though widely used in anticancer therapy, they are associated with cardiotoxic side-effects. The aim of this trial was to investigate long-term follow-up cardiotoxicity findings in patients treated with doxorubicin and concomitant metoprolol or enalapril 10 years earlier. PATIENTS AND METHODS: Overall, 147 patients were randomized into the treatment arms. A total of 125 patients treated with doxorubicin without evidence of heart disease at the start of chemotherapy were analyzed. They were followed-up for up to 10 years after treatment start. RESULTS AND CONCLUSION: A total of 47 patients completed the follow-up and 21 patients died, none due to cardiotoxicity events. Clinical signs of heart failure were not seen in any patients and no statistically significant differences between baseline and 10-year findings were seen for echocardiographic variables. No evidence of long-term cardiotoxicity was seen and nor metoprolol or enalapril offered an additional benefit.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Cardiotoxicidade/prevenção & controle , Doxorrubicina/efeitos adversos , Enalapril/uso terapêutico , Linfoma/tratamento farmacológico , Metoprolol/uso terapêutico , Adolescente , Antraciclinas/uso terapêutico , Antibióticos Antineoplásicos/uso terapêutico , Cardiotoxicidade/etiologia , Doxorrubicina/uso terapêutico , Ecocardiografia/métodos , Feminino , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Masculino , Estudos Prospectivos
7.
Chem Biol Interact ; 313: 108834, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31545955

RESUMO

The anthracycline doxorubicin (DOX) is widely used in cancer therapy with the limitation of cardiotoxicity leading to the development of congestive heart failure. DOX-induced oxidative stress and changes of the phosphoproteome as well as epigenome were described but the exact mechanisms of the adverse long-term effects are still elusive. Here, we tested the impact of DOX treatment on cell death, oxidative stress parameters and expression profiles of proteins involved in epigenetic pathways in a cardiomyocyte cell culture model. Markers of oxidative stress, apoptosis and expression of proteins involved in epigenetic processes were assessed by immunoblotting in cultured rat myoblasts (H9c2) upon treatment with DOX (1 or 5 µM for 24 or 48 h) in adherent viable and detached apoptotic cells. The apoptosis markers cleaved caspase-3 and fractin as well as oxidative stress markers 3-nitrotyrosine and malondialdehyde were dose-dependently increased by DOX treatment. Histone deacetylases (SIRT1 and HDAC2), histone lysine demethylases (KDM3A and LSD1) and histone lysine methyltransferases (SET7 and SMYD1) were significantly regulated by DOX treatment with generation of cleaved protein fragments and posttranslational modifications. Overall, we found significant decrease in histone 3 acetylation in DOX-treated cells. DOX treatment of cultured cardiomyocyte precursor cells causes severe cell death by apoptosis associated with cellular oxidative stress. In addition, significant regulation of proteins involved in epigenetic processes and changes in global histone 3 acetylation were observed. However, the significance and clinical impact of these changes remain elusive.


Assuntos
Doxorrubicina/efeitos adversos , Epigênese Genética/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos/efeitos adversos , Apoptose/efeitos dos fármacos , Apoptose/genética , Biomarcadores/metabolismo , Cardiotoxicidade/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Histona Desacetilases/metabolismo , Histona Desmetilases/metabolismo , Histonas/metabolismo , Peróxido de Hidrogênio/farmacologia , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos
8.
Int J Nanomedicine ; 14: 6061-6071, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534336

RESUMO

Background: Doxorubicin (DOX), a broad-spectrum chemotherapy drug, is clinically employed to treat cancers especially for breast cancer and lung cancer. But its clinical applications are limited by the dose-dependent cardiac toxicity. Resveratrol (Res), a polyphenolic antitoxin, has been proved to be capable of improving the cardiomyocyte calcium cycling by up-regulating SIRT-1-mediated deacetylation to inhibit DOX-induced cardiotoxicity. Purpose: The objective of this study was to develop a solid lipid nanoparticle (SLN) loaded with Res to trigger inhibition of DOX-induced cardiotoxicity. Methods: Res-SLN was prepared by emulsification-diffusion method followed by sonication and optimized using central composite design/response surface method. The Res-SLN was further evaluated by dynamic light scattering, transmission electron microscopy for morphology and high performance liquid chromatography for drug loading and release profile. And the Res distribution in vivo was determined on rats while the effect of inhibit DOX-induced cardiotoxicity was investigated on mice. Results: Res-SLN with homogeneous particle size of 271.13 nm was successfully formulated and optimized. The prepared Res-SLN showed stable under storage and sustained release profile, improving the poor solubility of Res. Heart rate, ejection fractions and fractional shortening of Res-SLN treating mice were found higher than those on mice with cardiac toxicity induced by single high-dose intraperitoneal injection of DOX. And the degree of myocardial ultrastructural lesions on mice was also observed. Conclusion: Res-SLN has a certain therapeutic effect for protecting the myocardium and reducing DOX-induced cardiotoxicity in mice.


Assuntos
Cardiotoxicidade/tratamento farmacológico , Doxorrubicina/efeitos adversos , Lipídeos/química , Nanopartículas/química , Resveratrol/uso terapêutico , Animais , Cardiotoxicidade/patologia , Feminino , Humanos , Masculino , Camundongos , Miocárdio/patologia , Nanopartículas/ultraestrutura , Ratos Sprague-Dawley , Resveratrol/química , Resveratrol/farmacocinética , Resveratrol/farmacologia
9.
Rinsho Ketsueki ; 60(8): 929-931, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31484892

RESUMO

A 51-year-old man was diagnosed with stage IV mantle cell lymphoma based on terminal ileum biopsy and treated with the R-CHOP regimen. Abdominal CT to assess continuous fever after three courses of R-CHOP revealed three low-density areas in the liver. PCR of the fluid obtained by percutaneous drainage revealed Entamoeba histolytica positivity, although the cultures were negative. Metronidazole treatment achieved cure. The patient was not a homosexual but had an 8-month stay in Lesotho 21 years ago, leading to the possibility that E. histolytica infection at the time continued as an asymptomatic colonization until the initiation of corticosteroid-containing chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Entamoeba histolytica , Abscesso Hepático Amebiano , Linfoma de Célula do Manto , Anticorpos Monoclonais Murinos/efeitos adversos , Ciclofosfamida/efeitos adversos , Doxorrubicina/efeitos adversos , Humanos , Abscesso Hepático Amebiano/induzido quimicamente , Linfoma de Célula do Manto/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prednisona/efeitos adversos , Rituximab , Vincristina/efeitos adversos
10.
Mol Pharmacol ; 96(4): 475-484, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31399497

RESUMO

Topoisomerase II (TOP2) poisons are effective cytotoxic anticancer agents that stabilize the normally transient TOP2-DNA covalent complexes formed during the enzyme reaction cycle. These drugs include etoposide, mitoxantrone, and the anthracyclines doxorubicin and epirubicin. Anthracyclines also exert cell-killing activity via TOP2-independent mechanisms, including DNA adduct formation, redox activity, and lipid peroxidation. Here, we show that anthracyclines and another intercalating TOP2 poison, mitoxantrone, stabilize TOP2-DNA covalent complexes less efficiently than etoposide, and at higher concentrations they suppress the formation of TOP2-DNA covalent complexes, thus behaving as TOP2 poisons at low concentration and inhibitors at high concentration. We used induced pluripotent stem cell (iPSC)-derived human cardiomyocytes as a model to study anthracycline-induced damage in cardiac cells. Using immunofluorescence, our study is the first to demonstrate the presence of topoisomerase IIß (TOP2B) as the only TOP2 isoform in iPSC-derived cardiomyocytes. In these cells, etoposide robustly induced TOP2B covalent complexes, but we could not detect doxorubicin-induced TOP2-DNA complexes, and doxorubicin suppressed etoposide-induced TOP2-DNA complexes. In vitro, etoposide-stabilized DNA cleavage was attenuated by doxorubicin, epirubicin, or mitoxantrone. Clinical use of anthracyclines is associated with cardiotoxicity. The observations in this study have potentially important clinical consequences regarding the effectiveness of anticancer treatment regimens when TOP2-targeting drugs are used in combination. These observations suggest that inhibition of TOP2B activity, rather than DNA damage resulting from TOP2 poisoning, may play a role in doxorubicin cardiotoxicity. SIGNIFICANCE STATEMENT: We show that anthracyclines and mitoxantrone act as topoisomerase II (TOP2) poisons at low concentration but attenuate TOP2 activity at higher concentration, both in cells and in in vitro cleavage experiments. Inhibition of type II topoisomerases suppresses the action of other drugs that poison TOP2. Thus, combinations containing anthracyclines or mitoxantrone and etoposide may reduce the activity of etoposide as a TOP2 poison and thus reduce the efficacy of drug combinations.


Assuntos
Antraciclinas/farmacologia , Adutos de DNA/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Etoposídeo/farmacologia , Mitoxantrona/farmacologia , Cardiotoxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Adutos de DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/efeitos adversos , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células K562 , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Inibidores da Topoisomerase II/farmacologia
11.
Life Sci ; 233: 116704, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31369761

RESUMO

AIMS: Doxorubicin, an anticancer drug, has a toxic effect on many tissues such as heart, pancreas, liver, kidney, and testis. The aim of current study is to investigate whether melatonin would be protective in doxorubicin-induced beta (ß) cell toxicity via HMGB1/TLR2/TLR4/MAPK/NF-қB signaling pathway. MAIN METHODS: Human pancreatic ß cell (1.1B4) was used in the present study. Four experimental groups were created as control, melatonin (10 µM), doxorubicin (2 µM) and the combination of melatonin with doxorubicin. Following 24-h treatment, Mitogen-activated protein kinase (MAPKs), Toll like receptors (TLRs) including TLR2 and TLR4, pro-and anti-apoptotic protein expression levels were determined by western blotting. Total antioxidant (TAS), oxidant status (TOS) and oxidative stress index (OSI) of the cells as well as superoxide dismutase (SOD) levels were determined. Active caspase-8 activity was measured and TUNEL staining was performed to study apoptotic pathways. Mitochondrial membrane potential (MMP), some protein expressions and F-actin distribution were analyzed. KEY FINDINGS: Doxorubicin caused to depolarize MMP, resulting in enhancing apoptosis by activation of caspase-8 via MAPKs/NF-кB pathway via elevation of TOS and decreasing TAS. Also, doxorubicin destroyed F-actin distribution and elevated TLR2 and some apoptotic proteins, including Bax. However, co-treatment of melatonin with doxorubicin could reverse depolarization of MMP and inhibition of apoptosis through MAPK/NF-кB signaling by decreasing TOS and increasing TAS. The co-treatment reversed the alternations of TLR2, TLR4, MAPKs and apoptotic protein expressions induced by doxorubicin. SIGNIFICANCE: Melatonin could be a good candidate against pancreatic ß cell toxicity-induced by doxorubicin through TLR2/TLR4/MAPK/NF-кB pathways.


Assuntos
Doxorrubicina/efeitos adversos , Células Secretoras de Insulina/efeitos dos fármacos , Melatonina/farmacologia , Substâncias Protetoras/farmacologia , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Antibióticos Antineoplásicos/efeitos adversos , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Proteína HMGB1/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NF-kappa B/metabolismo , Oxidantes/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
12.
Anticancer Res ; 39(8): 4379-4383, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366533

RESUMO

BACKGROUND/AIM: Dose-dense doxorubicin and cyclophosphamide (ddAC) followed by dose-dense paclitaxel (ddP) (ddAC-P) has improved disease-free survival of patients with breast cancer. The aim of this study was to evaluate the safety and relative dose intensity (RDI) of ddAC-P administered together with pegfilgrastim. PATIENTS AND METHODS: Between May 2015 and Aug 2017, 44 patients were retrospectively reviewed; they were administered 4 cycles of ddAC, followed by 4 cycles of ddP. Pegfilgrastim (3.6 mg) was administered in every cycle. RESULTS: The mean RDIs for ddAC-P, ddAC, and ddP were 95.0%, 94.5%, and 93.3%, respectively. The prevalence of high RDIs (≥85%) for ddAC-P, ddAC, and ddP was 90.9%, 84.1%, and 88.6%, respectively. Seven of the 10 patients with low RDIs experienced grade 1 or 2 fever. CONCLUSION: DdAC-P administered together with pegfilgrastim (3.6 mg) appears to be feasible and maintains RDI in most of Japanese patients with breast cancer. Rapid evaluation and proper management of fever may prevent low RDI.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Paclitaxel/administração & dosagem , Adulto , Idoso , Neoplasias da Mama/patologia , Ciclofosfamida/efeitos adversos , Relação Dose-Resposta a Droga , Doxorrubicina/efeitos adversos , Feminino , Filgrastim/administração & dosagem , Humanos , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Polietilenoglicóis/administração & dosagem
13.
Can J Physiol Pharmacol ; 97(9): 880-884, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31365282

RESUMO

The objective of this study was to analyze the cardioprotective roles of 3 wild blueberry genotypes and one commercial blueberry genotype by measuring markers of oxidative stress and cell death in H9c2 cardiac cells exposed to doxorubicin. Ripe berries of the 3 wild blueberry genotypes were collected from a 10-year-old clearcut forest near Nipigon, Ontario, Canada (49°1'39″N, 87°52'21″W), whereas the commercial blueberries were purchased from a local grocery store. H9c2 cardiac cells were incubated with 15 µg gallic acid equivalent/mL blueberry extract for 4 h followed by 5 µM doxorubicin for 4 h, and oxidative stress and active caspase 3/7 were analyzed. The surface area as well as total phenolic content was significantly higher in all 3 wild blueberry genotypes compared with the commercial species. Increase in oxidative stress due to doxorubicin exposure was attenuated by pre-treatment with all 3 types of wild blueberries but not by commercial berries. Furthermore, increase in caspase 3/7 activity was also attenuated by all 3 wild genotypes as well. These data demonstrate that wild blueberry extracts can attenuate doxorubicin-induced damage to H9c2 cardiomyocytes through reduction in oxidative stress and apoptosis, whereas the commercial blueberry had little effect.


Assuntos
Mirtilos Azuis (Planta)/química , Citoproteção/efeitos dos fármacos , Doxorrubicina/efeitos adversos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fenóis/análise , Extratos Vegetais/química , Ratos
14.
Am J Chin Med ; 47(5): 1075-1097, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31311298

RESUMO

Pirarubicin (THP) is an anthracycline antibiotic, frequently used for the treatment of various human cancers. Unfortunately, the clinical effectiveness of THP is limited by its dose-related cardiotoxicity. Apocynum leaf extract is an extract of the dried leaves of Apocynum venetum L. (a member of the Apocynaceae family, AVLE) that has many positive effects on the cardiovascular system and is widely consumed as tea in China. In this study we established a cardiactoxicity rat model, which showed that pretreatment with AVLE attenuated THP-induced myocardial histopathological injury, electrocardiogram abnormalities, and cardiac dysfunction. AVLE also significantly reduced serum levels of malondialdehyde (MDA), brain natriuretic peptide (BNP), creatine kinase (CK-MB), cardiac troponin (CTnT), and lactate dehydrogenase (LDH); and increased serum superoxide dismutase (SOD) levels. Treatment with AVLE or dexrazoxane (DZR) resulted in an increase Cytochrome C (cytc) in the mitochondria and reduced Cytc and cleaved-caspase-3 levels (p<0.05) in cytoplasm. We also found that AVLE significantly reduced voltage-dependent anion channel 1 (VDAC1), adenosine nucleotide transporter 1 (ANT1), and cyclophilin D (CYPD) mRNA expression (p<0.05). Furthermore, AVLE appeared to exert therapeutic effects in a dose-dependent manner. Our study suggests the anti-oxidant and anti-apoptotic properties of AVLE may be responsible for the observed cardioprotective effects.


Assuntos
Antioxidantes/administração & dosagem , Apocynum/química , Cardiotoxicidade/prevenção & controle , Medicamentos de Ervas Chinesas/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Cardiotoxicidade/fisiopatologia , Creatina Quinase/genética , Creatina Quinase/metabolismo , Doxorrubicina/efeitos adversos , Doxorrubicina/análogos & derivados , Humanos , Masculino , Malondialdeído/metabolismo , Peptídeo Natriurético Encefálico/genética , Peptídeo Natriurético Encefálico/metabolismo , Folhas de Planta/química , Ratos , Ratos Wistar , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Troponina/genética , Troponina/metabolismo
15.
Life Sci ; 232: 116623, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279781

RESUMO

AIMS: Doxorubicin, an antibiotic belonging to anthracycline family, has been used for treatment of malignancies. Cardiotoxicity is the main adverse effect of doxorubicin. Apigenin, as a flavonoid, has antioxidant, anti-inflammatory and anti-tumoral properties. The aim of this study was the assessment of any protective effect of apigenin on cardiotoxicity induced by doxorubicin. MAIN METHODS: 40 male Wistar rats were randomly divided into 4 groups: control, cardiotoxicity (DOX), apigenin treated group (DOX + Api 25) and apigenin group (Api 25). At the end of the experiment, the markers of cardiac function (%EF, %FS, LVIDs, LVIDd), cardiac and liver injury (LDH, CK-MB, cTn-I, ALT, and AST), cardiac apoptosis (Bax, Bcl-2 and Caspase3), cardiac oxidative stress (SOD, GSH, MDA) and cardiac fibrosis were measured. KEY FINDINGS: Apigenin improved cardiac functional parameters. The levels of cardiac and liver injury markers were significantly decreased in DOX + Api 25 compared to DOX. Treatment with apigenin caused significant decrease in percentage of cardiac fibrosis in comparison with DOX. Apigenin in DOX + Api 25 group led to significant decrease in apoptotic proteins (Casp3, Bax) and a significant increase in anti-apoptotic proteins (Bcl2). In apigenin treatment groups, SOD levels significantly increased while a significant decrease was observed in MDA. The amount of GSH in DOX + Api 25 had no significant change in comparison to control and Api 25 groups. SIGNIFICANCE: Apigenin reduced cardiac injuries induced by DOX through anti-fibrotic, antioxidant and anti-apoptotic properties. It seems that apigenin prevents cardiac injuries and improves cardiac function.


Assuntos
Apigenina/farmacologia , Cardiotoxicidade/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Apigenina/metabolismo , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Doxorrubicina/efeitos adversos , Doxorrubicina/metabolismo , Flavonoides/farmacologia , Testes de Função Cardíaca , Inflamação/patologia , Masculino , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
16.
Integr Cancer Ther ; 18: 1534735419862351, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31282195

RESUMO

Background: This study evaluated the cardioprotective effect of Ajwa nano-preparation against doxorubicin-associated cardiotoxicity. Methods: Twenty-four male Wistar rats (200-250 g) were divided into 3 groups. One group was given the nanopreparation containing both Ajwa fruit and pit in a dose of 1.4 g/kg orally 1 hour before doxorubicin infusion (Dates-DOX group). Another group was given the vehicle for 1 hour before doxorubicin infusion (DOX group). The third group received the vehicle but no DOX infusion (time control). Cardiac hemodynamics, blood pressure, cardiac contractility, and conductivity were recorded before and after 45 minutes of infusion of doxorubicin (15 mg/kg, slow intravenous over 45 minutes). Blood samples were collected before and after doxorubicin infusion. Heart tissue samples were collected and snap frozen until assay of reduced glutathione. Results: Rats pre-administered Ajwa nanopreparation were protected from doxorubicin-associated systolic and diastolic dysfunction based on the significant elevation in the rate of rise in left ventricular pressure (dp/dtmax) and (dp/dtmin) compared with the DOX group. In addition, it prevented the doxorubicin-associated ischemia based on the significant shortening in QT interval, JT interval, and Tpeak-Tend interval versus the DOX group. There was no effect on atrial conductivity (PR interval and P duration). Ajwa pretreatment increased the antioxidant capacity of cardiac tissue, as evidenced by increasing the cardiac content of reduced glutathione compared with the untreated doxorubicin group. Conclusion: Ajwa nanopreparation protects from doxorubicin-associated cardiotoxicity through alleviating cardiac ischemia and increasing cardiac antioxidant capacity.


Assuntos
Antioxidantes/metabolismo , Doxorrubicina/efeitos adversos , Cardiopatias/induzido quimicamente , Cardiopatias/tratamento farmacológico , Coração/efeitos dos fármacos , Nanopartículas/administração & dosagem , Preparações de Plantas/farmacologia , Animais , Antibióticos Antineoplásicos/efeitos adversos , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/metabolismo , Frutas/química , Glutationa/metabolismo , Cardiopatias/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Phoeniceae/química , Ratos , Ratos Wistar
17.
G3 (Bethesda) ; 9(8): 2637-2646, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31263061

RESUMO

Anthracyclines cause progressive cardiotoxicity whose ultimate severity is individual to the patient. Genetic determinants contributing to this variation are difficult to study using current mouse models. Our objective was to determine whether a spectrum of anthracycline induced cardiac disease can be elicited across 10 Collaborative Cross mouse strains given the same dose of doxorubicin. Mice from ten distinct strains were given 5 mg/kg of doxorubicin intravenously once weekly for 5 weeks (total 25 mg/kg). Mice were killed at acute or chronic timepoints. Body weight was assessed weekly, followed by terminal complete blood count, pathology and a panel of biomarkers. Linear models were fit to assess effects of treatment, sex, and sex-by-treatment interactions for each timepoint. Impaired growth and cardiac pathology occurred across all strains. Severity of these varied by strain and sex, with greater severity in males. Cardiac troponin I and myosin light chain 3 demonstrated strain- and sex-specific elevations in the acute phase with subsequent decline despite ongoing progression of cardiac disease. Acute phase cardiac troponin I levels predicted the ultimate severity of cardiac pathology poorly, whereas myosin light chain 3 levels predicted the extent of chronic cardiac injury in males. Strain- and sex-dependent renal toxicity was evident. Regenerative anemia manifested during the acute period. We confirm that variable susceptibility to doxorubicin-induced cardiotoxicity observed in humans can be modeled in a panel of CC strains. In addition, we identified a potential predictive biomarker in males. CC strains provide reproducible models to explore mechanisms contributing to individual susceptibility in humans.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Cardiotoxicidade/etiologia , Doxorrubicina/efeitos adversos , Animais , Antibióticos Antineoplásicos/uso terapêutico , Biomarcadores , Biópsia , Cardiotoxicidade/mortalidade , Cruzamentos Genéticos , Modelos Animais de Doenças , Doxorrubicina/uso terapêutico , Feminino , Fibrose , Cardiopatias/diagnóstico , Cardiopatias/etiologia , Humanos , Masculino , Camundongos
18.
Eur J Pharmacol ; 859: 172542, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31319070

RESUMO

Nicorandil is an adenosine triphosphate-sensitive potassium channel opener with additional antioxidant properties. Doxorubicin (DOX) is an anticancer drug that exerts oxidation-mediated adverse cardiovascular effects. This study examined the effects of nicorandil on DOX-induced cytotoxicity in human umbilical vein endothelial cells (HUVECs) and underlying intracellular signaling mechanisms. Cultured HUVECs were pretreated with nicorandil (0.1, 0.3, 1, 3, and 10 µM) for 12 h and then treated with DOX (1 µM) for 24 h. Cell viability and cytotoxicity were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays, respectively. Cell apoptosis was examined using a caspase-3 activity assay, and DNA fragmentation was detected through TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) staining. Western blot analysis was conducted to determine the related protein expression. DOX markedly increased reactive oxygen species production, p53 expression, caspase-3 activity, cleaved caspase-3 levels, and TUNEL-positive cell numbers but reduced Bcl-2 expression and intracellular antioxidant enzyme levels; these effects were effectively antagonized through nicorandil (3 µM, 12 h) pretreatment, which resulted in HUVECs being protected from DOX-induced apoptosis. Activating transcription factor 3 (ATF3), a stress-induced transcription factor, was induced by nicorandil (3 µM). Furthermore, nicorandil (3 µM) enhanced nuclear factor erythroid 2-related factor 2 (Nrf2) translocation and heme oxygenase-1 (HO-1) expression. ATF3 short interfering RNA significantly attenuated nicorandil-mediated Nrf2 translocation, HO-1 expression, and inhibitory effects on DOX-stimulated reactive oxygen species production and cell apoptosis. In summary, nicorandil may protect HUVECs from DOX-induced apoptosis, in part through ATF3-mediated Nrf2/HO-1 signaling pathways, which potentially protect the vessels from severe DOX toxicity.


Assuntos
Apoptose/efeitos dos fármacos , Doxorrubicina/efeitos adversos , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Nicorandil/farmacologia , Fator 3 Ativador da Transcrição/metabolismo , Antioxidantes/metabolismo , Citoproteção/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo
19.
Artigo em Inglês | MEDLINE | ID: mdl-31280244

RESUMO

Background Doxorubicin (DOX) induces toxicity in many tissues/organs, including the heart, kidney and so on. This study was designed to evaluate the modulatory effects of protocatechuic acid (PCA) against DOX-induced nephrotoxicity in rats. Animals were randomly grouped into five groups. Methods Group 1 served as the normal control (CTR). A single dose of DOX at 20 mg/kg was administered intraperitoneally (i.p.) to animals in Group 2. Groups 3 and 4 were pretreated with PCA for 5 days (doses of 10 and 20 mg/kg body weight, respectively) after which DOX was injected (PCA-10 + DOX and PCA-20 + DOX). Group 5 received PCA only at a dose of 20 mg/kg body weight (PCA-20). Results The results revealed significant elevations (p < 0.05) in malondialdehyde content, expressions of inducible nitric oxide (iNOS) and cyclooxygenase-2 (COX2) in the kidney. Likewise, increased serum levels of creatinine and urea of DOX group were observed. A significant decrease (p < 0.05) in glutathione (GSH) level and antioxidant enzymes: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione s- transferase (GST) activities in the kidney were observed compared with the control. Pretreatment with PCA (10 and 20 mg/kg, p.o.) for 5 days prior to the i.p. injection of DOX reduced MDA levels, modulated iNOS and COX2 activities and improved kidney function markers as well as oxidative stress parameters. Findings from the histopathology studies confirms the protective effects of PCA on DOX-induced damage on the kidney cells. Conclusions This study has demonstrated the anti-inflammatory and antioxidative properties of PCA, which could be part of its possible protective mechanisms against nephrotoxicity induced by DOX.


Assuntos
Doxorrubicina/efeitos adversos , Hidroxibenzoatos/farmacologia , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Rim/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Antioxidantes/farmacologia , Biomarcadores/metabolismo , Creatinina/metabolismo , Modelos Animais de Doenças , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Malondialdeído/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo
20.
Biomed Res Int ; 2019: 1528278, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31355248

RESUMO

Oxidative stress and cardiomyocytes apoptosis were closely involved in the pathological process of doxorubicin- (Dox-) induced cardiac injury. MicroRNA-451 (miR-451) was mainly expressed in cardiomyocytes. However, the role of miR-451 in Dox-induced cardiac injury remained unclear. Our study aimed to investigate the effect of miR-451 on Dox-induced cardiotoxicity in mice. We established a Dox-induced cardiotoxicity model in the mice and manipulated miR-451 expression in the heart using a miR-451 inhibitor, which was injected every other day beginning at one day before Dox injection. Oxidative stress and apoptosis in the hearts were evaluated. miR-451 levels were significantly increased in Dox-treated mice or cardiomyocytes. miR-451 inhibition attenuated Dox-induced whole-body wasting and heart atrophy, reduced cardiac injury, restored cardiac function, and improved cardiomyocyte contractile function. Moreover, miR-451 inhibition reduced oxidative stress and cardiomyocytes apoptosis in vivo and in vitro. miR-451 inhibition increased the expression of calcium binding protein 39 (Cab39) and activated adenosine monophosphate activated protein kinase (AMPK) signaling pathway. A specific inhibitor of AMPK abolished the protection provided by miR-451 inhibition against cell injury in vitro. In conclusion, miR-451 inhibition protected against Dox-induced cardiotoxicity via activation of AMPK signaling pathway.


Assuntos
Cardiotoxicidade/genética , Traumatismos Cardíacos/genética , MicroRNAs/genética , Estresse Oxidativo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade/patologia , Modelos Animais de Doenças , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Traumatismos Cardíacos/induzido quimicamente , Traumatismos Cardíacos/patologia , Humanos , Camundongos , MicroRNAs/antagonistas & inibidores , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Quinases/genética , Transdução de Sinais/efeitos dos fármacos
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