topics / مواضيع

Abstract

Background: Myocardial injury caused by myocardial ischemia (MI) is still a severe condition that can result in apoptosis, oxidative stress, and inflammation. Remifentanil is a selective, ultra-short-acting, µ-opioid receptor agonist opioid. It can improve sinusoidal heart rate patterns in the fetus, for bupivacaine-induced cardiotoxicity, and with lipopolysaccharide (LPS)-induced cardiomyocytes injuries. This study aimed to explore the cardioprotective effects of remifentanil in MI model rats.

Methods: Sprague Dawley (SD) rats were split into five groups at random, including a control group, Isop group, low-dose remifentanil treatment group (10 µg/kg), medium-dose remifentanil treatment group (20 µg/kg), and a high-dose remifentanil treatment group (40 µg/kg). The MI model was achieved by subcutaneously injecting rats with isoproterenol (85 mg/kg) for two consecutive days. With the expression of apoptotic molecules, myocardial systolic function index, inflammation, antioxidant enzymes, and the myocardial enzyme taken into account, the data was analyzed.

Results: After treatment with remifentanil, the left ventricular wall thickness (LVWT), left ventricular end-systolic volume (LVESV), left ventricular ejection fraction (LVEF), fraction shortening (FS), and heart rate (HR) were significantly increased in comparison with the Isop group. Creatine kinase-MB (CK-MB), Mb, and cTnl expressions were decreased. Meanwhile, the levels of cleaved caspase-3 and caspase-9 were decreased. Remarkably, the levels of reactive oxidative species (ROS), malondialdehyde (MDA), and lactate dehydrogenase (LDH) were observed to be repressed, while the levels of superoxide dismutase (SOD) was significantly increased. More importantly, the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and interferon (IFN)-γ were decreased.

Conclusions: Remifentanil has significant potential as a therapeutic intervention strategy for ameliorating myocardial injury after MI and these findings provide the rationale for further clinical studies.

PMID: 32411774 [PubMed]

10:46

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pubmed: tutte cardiotoxicity...

High Density Lipoprotein and Its Precursor Protein Apolipoprotein A1 as Potential Therapeutics to Prevent Anthracycline Associated Cardiotoxicity.

Front Cardiovasc Med. 2020;7:65

Authors: Kluck GEG, Durham KK, Yoo JA, Trigatti BL

Abstract

Cardiovascular disease and cancer are the leading causes of death in developed societies. Despite their effectiveness, many cancer therapies exhibit deleterious cardiovascular side effects such as cardiotoxicity and heart failure. The cardiotoxic effects of anthracyclines such as doxorubicin are the most well-characterized of cardiotoxic anti-cancer therapies. While other anti-neoplastic drugs also induce cardiotoxicity, often leading to heart failure, they are beyond the scope of this review. This review first summarizes the mechanisms of doxorubicin-induced cardiotoxicity. It then reviews emerging preclinical evidence that high density lipoprotein and its precursor protein apolipoprotein A1, which are known for their protective effects against ischemic cardiovascular disease, may also protect against doxorubicin-induced cardiotoxicity both directly and indirectly, when used therapeutically.

PMID: 32411725 [PubMed]

10:46

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Anthracycline-induced cardiotoxicity: mechanisms of action, incidence, risk factors, prevention, and treatment.

Heart Fail Rev. 2020 May 14;:

Authors: Saleh Y, Abdelkarim O, Herzallah K, Abela GS

Abstract

Anthracycline is a mainstay in treatment of many cancers including lymphoma and breast cancer among many others. However, anthracycline treatment can be cardiotoxic. Although anthracycline-induced cardiotoxicity is dose dependent, it can also occur early at the onset of treatment and even up to several years following completion of treatment. This review article focuses on the understanding of mechanisms of anthracycline-induced cardiotoxicity, the treatments, and recommended follow-up and preventive approaches.

PMID: 32410142 [PubMed - as supplied by publisher]

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Anti-HER2 therapy-associated cardiotoxicity in breast cancer patients: analysis of real-world data from a UK cancer centre.

Clin Med (Lond). 2020 Mar;20(Suppl 2):s20

Authors: Efthymiadis A, Teoh M

PMID: 32409347 [PubMed - in process]

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pubmed: tutte cardiotoxicity...

Sex differences in anthracycline-induced cardiotoxicity: the benefits of estrogens.

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Sex differences in anthracycline-induced cardiotoxicity: the benefits of estrogens.

Heart Fail Rev. 2019 11;24(6):915-925

Authors: Cadeddu Dessalvi C, Pepe A, Penna C, Gimelli A, Madonna R, Mele D, Monte I, Novo G, Nugara C, Zito C, Moslehi JJ, de Boer RA, Lyon AR, Tocchetti CG, Mercuro G

Abstract

Anthracyclines are the cornerstone for many oncologic treatments, but their cardiotoxicity has been recognized for several decades. Female subjects, especially before puberty and adolescence, or after menopause, seem to be more at increased risk, with the prognostic impact of this sex issue being less consistent compared to other cardiovascular risk factors. Several studies imply that sex differences could depend on the lack of the protective effect of sex hormones against the anthracycline-initiated damage in cardiac cells, or on differential mitochondria-related oxidative gene expression. This is also reflected by the results obtained with different diagnostic methods, such as cardiovascular biomarkers and imaging techniques (echocardiography, magnetic resonance, and nuclear medicine) in the diagnosis and monitoring of cardiotoxicity, confirming that sex differences exist. The same is true about protective strategies from anthracycline cardiotoxicity. Indeed, first studied to withstand oxidative damage in response to ischemia/reperfusion (I/R) injury, cardioprotection has different outcomes in men and women. A number of studies assessed the differences in I/R response between male and female hearts, with oxidative stress and apoptosis being shared mechanisms between the I/R and anthracyclines heart damage. Sex hormones can modulate these mechanisms, thus confirming their importance in the pathophysiology in cardioprotection not only from the ischemia/reperfusion damage, but also from anthracyclines, fueling further cardio-oncologic research on the topic.

PMID: 31256318 [PubMed - indexed for MEDLINE]

18 May 2020

11:41

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Doxorubicin sensitizes cancer cells to Smac mimetic via synergistic activation of the CYLD/RIPK1/FADD/caspase-8-dependent apoptosis.

Apoptosis. 2020 May 16;:

Authors: Yang C, Ran Q, Zhou Y, Liu S, Zhao C, Yu X, Zhu F, Ji Y, Du Q, Yang T, Zhang W, He S

Abstract

Smac/Diablo is a pro-apoptotic protein via interaction with inhibitors of apoptosis proteins (IAPs) to relieve their inhibition of caspases. Smac mimetic compounds (also known as antagonists of IAPs) mimic the function of Smac/Diablo and sensitize cancer cells to TNF-induced apoptosis. However, the majority of cancer cells are resistant to Smac mimetic alone. Doxorubicin is a widely used chemotherapeutic drug and causes adverse effect of cardiotoxicity in many patients. Therefore, it is important to find strategies of combined chemotherapy to increase chemosensitivity and reduce the adverse effects. Here, we report that doxorubicin synergizes with Smac mimetic to trigger TNF-mediated apoptosis, which is mechanistically distinct from doxorubicin-induced cell death. Doxorubicin sensitizes cancer cells including human pancreatic and colorectal cancer cells to Smac mimetic treatment. The combined treatment leads to synergistic induction of TNFα to initiate apoptosis through activating NF-κB and c-Jun signaling pathways. Knockdown of caspase-8 or knockout of FADD significantly blocked apoptosis synergistically induced by Smac mimetic and doxorubicin, but had no effect on cell death caused by doxorubicin alone. Moreover, Smac mimetic and doxorubicin-induced apoptosis requires receptor-interacting protein kinase 1 (RIPK1) and its deubiquitinating enzyme cylindromatosis (CYLD), not A20. These in vitro findings demonstrate that combination of Smac mimetic and doxorubicin synergistically triggers apoptosis through the TNF/CYLD/RIPK1/FADD/caspase-8 signaling pathway. Importantly, the combined treatment induced in vivo synergistic anti-tumor effects in the xenograft tumor model. Thus, the combined therapy using Smac mimetic and doxorubicin presents a promising apoptosis-inducing strategy with great potential for the development of anti-cancer therapy.

PMID: 32418059 [PubMed - as supplied by publisher]

19 May 2020

12:19

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Outcome and Late Complications of Hepatoblastomas Treated Using the Japanese Study Group for Pediatric Liver Tumor 2 Protocol.

J Clin Oncol. 2020 May 18;:JCO1901067

Authors: Hiyama E, Hishiki T, Watanabe K, Ida K, Ueda Y, Kurihara S, Yano M, Hoshino K, Yokoi A, Takama Y, Nogami Y, Taguchi T, Mori M, Kihira K, Miyazaki O, Fuji H, Honda S, Iehara T, Kazama T, Fujimura J, Tanaka Y, Inoue T, Tajiri T, Kondo S, Oue T, Yoshimura K

Abstract

PURPOSE: We report here the outcomes and late effects of the Japanese Study Group for Pediatric Liver Tumors (JPLT)-2 protocol, on the basis of cisplatin-tetrahydropyranyl-adriamycin (CITA) with risk stratification according to the pretreatment extent of disease (PRETEXT) classification for hepatoblastoma (HB).

PATIENTS AND METHODS: From 1999 to 2012, 361 patients with untreated HB were enrolled. PRETEXT I/II patients were treated with up-front resection, followed by low-dose CITA (stratum 1) or received low-dose CITA, followed by surgery and postoperative chemotherapy (stratum 2). In the remaining patients, after 2 cycles of CITA, responders received the CITA regimen before resection (stratum 3), and nonresponders were switched to ifosfamide, pirarubicin, etoposide, and carboplatin (ITEC; stratum 4). Intensified chemotherapeutic regimens with autologous hematopoietic stem-cell transplantation (SCT) after resection were an optional treatment for patients with refractory/metastatic disease.

RESULTS: The 5-year event-free and overall survival rates of HB patients were 74.2% and 89.9%, respectively, for stratum 1, 84.8% and 90.8%%, respectively, for stratum 2, 71.6% and 85.9%%, respectively, for stratum 3, and 59.1% and 67.3%%, respectively, for stratum 4. The outcomes for CITA responders were significantly better than those for nonresponders, whose outcomes remained poor despite salvage therapy with a second-line ITEC regimen or SCT. The late effects, ototoxicity, cardiotoxicity, and delayed growth, occurred in 61, 18, and 47 patients, respectively. Thirteen secondary malignant neoplasms (SMNs), including 10 leukemia, occurred, correlating with higher exposure to pirarubicin and younger age at diagnosis.

CONCLUSION: The JPLT-2 protocol achieved up-front resectability in PRETEXT I/II patients with no annotation factors, and satisfactory survival in patients who were CITA responders in the remaining patients. However, outcomes for CITA nonresponders were unsatisfactory, despite therapy intensification with ITEC regimens and SCT. JPLT-2 had a relatively low incidence of cardiotoxicity but high rates of SMNs.

PMID: 32421442 [PubMed - as supplied by publisher]

12:19

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Therapeutic Effects of Liraglutide, Oxytocin and Granulocyte Colony-Stimulating Factor in Doxorubicin-Induced Cardiomyopathy Model: An Experimental Animal Study.

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Therapeutic Effects of Liraglutide, Oxytocin and Granulocyte Colony-Stimulating Factor in Doxorubicin-Induced Cardiomyopathy Model: An Experimental Animal Study.

Cardiovasc Toxicol. 2019 12;19(6):510-517

Authors: Taşkıran E, Erdoğan MA, Yiğittürk G, Erbaş O

Abstract

Doxorubicin-induced (DXR) cardiomyopathy is a serious health issue in oncology patients. Effective treatment of this clinical situation still remains to be discovered. In this experimental animal study, we aimed to define therapeutic effects of liraglutide, oxytocin and granulocyte colony-stimulating factor in DXR-induced cardiomyopathy model. 40 male Sprague-Dawley rats were included to study. 32 rats were given doxorubicin (DXR) for cardiomyopathy model. DXR was administered intraperitonally (i.p.) at every other day of 2.5 mg/kg/day at six times. Eight rats were taken as normal group and no treatment was performed. 32 rats given doxorubicin were divided into 4 groups. Group 1 rats were assigned to a placebo group and was given with a 0.9% NaCl saline solution at a dose of 1 ml/kg/day i.p. (DXR + saline), Group 2 rats were given with 1.8 mg/kg/day of Liraglutide i.p. (DXR + LIR), Group 3 rats were given with 160 μg/kg/day oxytocin i.p. (DXR + OX), Group 4 rats were given with 100 μg/kg/day filgrastim i.p. (DXR + G-CSF). All medications were given for 15 days. On day 16, under anesthesia, ECG was recorded from derivation I. After that, blood samples were taken by tail vein puncture for biochemical analysis. Finally, the animals were euthanized and the heart removed and prepared for immunohistochemical examination. All three treatments were shown to ameliorate the toxic effect of doxorubicin in cardiac tissue with the best results in DXR + OX group. DXR + OX group had the most preserved tissue integrity examined by light microscopy, least immune expression level of CASPASE-3 (5.3 ± 0.9) (p < 0.001)< 0.00001)< 0.001),< 0.001),< 0.001),< 0.001),< 0.001)

PMID: 31054117 [PubMed - indexed for MEDLINE]

12:19

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pubmed: tutte cardiotoxicity...

Break a sweat to reduce cardiotoxicity - the benefits of exercise training during anthracycline chemotherapy.

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Break a sweat to reduce cardiotoxicity - the benefits of exercise training during anthracycline chemotherapy.

Eur J Prev Cardiol. 2019 02;26(3):301-304

Authors: Lyon AR, Habibian M

PMID: 30616383 [PubMed - indexed for MEDLINE]

20 May 2020

16:05

Cardiotoxicity News

pubmed: tutte cardiotoxicity...

Serum miR-222-3p as a Double-Edged Sword in Predicting Efficacy and Trastuzumab-Induced Cardiotoxicity for HER2-Positive Breast Cancer Patients Receiving Neoadjuvant Target Therapy.

Front Oncol. 2020;10:631

Authors: Zhang S, Wang Y, Wang Y, Peng J, Yuan C, Zhou L, Xu S, Lin Y, Du Y, Yang F, Zhang J, Dai H, Yin W, Lu J

Abstract

Background: We aimed to explore whether the expression of serum miR-222-3p might contribute to early prediction of therapeutic response, clinical outcomes, and adverse events for HER2-positive breast cancer patients receiving neoadjuvant therapy (NAT). Methods: A total of 65 HER2-positive breast cancer patients receiving NAT were analyzed. The concentration of serum miR-222-3p was detected by quantitative real-time PCR. Logistic regression analysis was used to identify the association of serum miR-222-3p with pathological complete response (pCR). The relationship of serum miR-222-3p with disease-free survival (DFS) and overall survival (OS) was examined via log-rank test and Cox proportional hazards analysis. The ordered logistic regression was applied to evaluate the association between serum miR-222-3p and adverse events. Results: The miR-222-3p low group was more likely to achieve pCR [odds ratio (OR) = 0.258, P = 0.043]. The interaction between miR-222-3p and presenting Ki67 level was also detected for pCR (OR = 49.230, P interaction = 0.025). The miR-222-3p low group was correlated with superior DFS (P = 0.029) and OS (P = 0.0037). The expression of serum miR-222-3p was the independent protective factor for trastuzumab-induced cardiotoxicity (P < 0.05) and anemia (P = 0.013). Conclusions: Serum miR-222-3p is the potential factor to predict pCR, survival benefit and trastuzumab-induced cardiotoxicity for HER2-positive breast cancer patients receiving NAT.

PMID: 32426280 [PubMed]

21 May 2020

12:27

Cardiotoxicity News

pubmed: tutte cardiotoxicity...

Pivarubicin is more effective than doxorubicin against triple-negative breast cancer in vivo.

Oncol Res. 2020 May 15;:

Authors: Lothstein L, Soberman J, Parke D, Gandhi J, Sweatman T, Seagroves T

Abstract

Triple-negative breast cancer (TNBC) is unresponsive to anti-estrogen and anti-HER2 therapies, requiring the use of cytotoxic drug combinations of anthracyclines, taxanes, cyclophosphamide and platinum compounds. Multidrug therapies achieve pathological cure rates of only 20-40%; a consequence of drug resistance and cumulative dose limitations necessitated by the irreversible cardiotoxic effects of drug therapy. Safer and more effective treatments for TNBC are required to achieve durable therapeutic responses. This study describes the mechanistic analyses of the novel anthracycline, pivarubicin, and its in vivo efficacy against human primary TNBC.

Pivarubicin directly activates PKC-delta, triggers rapid mitochondrial-dependent apoptosis and circumvents resistance conferred by overexpression of P-glycoprotein, Bcl-2, Bcl-XL and Bcr-Abl. As a consequence, pivarubicin is more cytotoxic than doxorubicin against MDA-MB-231 and SUM159 TNBC cell lines grown in both monolayer culture and tumorspheres. Comparative in vivo efficacy of pivarubicin and doxorubicin was performed in an orthotopic NSG mouse model implanted with MDA-MB-231 human TNBC cells and treated with the maximum tolerated doses (MTD) of pivarubicin and doxorubicin. Tumor growth was monitored by digital caliper measurements and determination of endpoint tumor weight and volume. Endpoint cardiotoxicity was assessed histologically by identifying microvacuolization in ventricular cardiomyocytes.

Primary tumors treated with the multiple rounds of doxorubicin at MTD failed to inhibit tumor growth compared with vehicle-treated tumors. However, administration of a single MTD of pivarubicin produced significant inhibition of tumor growth and tumor regression relative to tumor volume prior to initiation of treatment. Histological analysis of hearts excised from drug- and vehicle-treated mice revealed that pivarubicin produced no evidence of myocardial damage at a therapeutic dose. These results support the development of pivarubicin as a safer and more effective replacement for doxorubicin against TNBC as well as other malignancies for which doxorubicin therapy is indicated.

PMID: 32430093 [PubMed - as supplied by publisher]

12:28

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Maduramicin induces cardiac muscle cell death by the ROS-dependent PTEN/Akt-Erk1/2 signaling pathway.

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Maduramicin induces cardiac muscle cell death by the ROS-dependent PTEN/Akt-Erk1/2 signaling pathway.

J Cell Physiol. 2019 07;234(7):10964-10976

Authors: Chen X, Li Y, Feng M, Hu X, Zhang H, Zhang R, Dong X, Liu C, Zhang Z, Jiang S, Huang S, Chen L

Abstract

Maduramicin (Mad), a polyether ionophore antibiotic, has been reported to be toxic to animals and humans because of being used at high doses or for long time, resulting in heart failure. However, the toxic mechanism of Mad in cardiac muscle cells is not well understood. Here, we show that Mad induced cell viability reduction and apoptosis in cardiac-derived H9c2, HL-1 cells, primary cardiomyocytes, and murine cardiac muscles, which was because of the inhibition of extracellular-signal-regulated kinase 1/2 (Erk1/2). Expression of constitutively active mitogen-activated protein kinase kinase 1 (MKK1) attenuated Mad-induced cell death in H9c2 cells, whereas silencing Erk1/2 or ectopic expression of dominant negative MKK1 strengthened Mad-induced cell death. Moreover, we found that both phosphatase and tensin homolog on chromosome 10 (PTEN) and protein kinase B (Akt) were implicated in the regulation of Erk1/2 inactivation and apoptosis in the cells and tissues exposed to Mad. Overexpression of dominant negative PTEN and/or constitutively active Akt, or constitutively active Akt and/or constitutively active MKK1 rescued the cells from Mad-induced dephosphorylated-Erk1/2 and cell death. Furthermore, Mad-induced reactive oxygen species (ROS) activated PTEN and inactivated Akt-Erk1/2 contributing to cell death, as N-acetyl- L-cysteine ameliorated the event. Taken together, the results disclose that Mad inhibits Erk1/2 via ROS-dependent activation of PTEN and inactivation of Akt, leading to cell death in cardiac muscle cells. Our findings suggest that manipulation of the ROS-PTEN-Akt-Erk1/2 pathway may be a potential approach to prevent Mad-induced cardiotoxicity.

PMID: 30511398 [PubMed - indexed for MEDLINE]

22 May 2020

13:11

Cardiotoxicity News

pubmed: tutte cardiotoxicity...

Fluoropyrimidine-Associated Cardiotoxicity: Probably Not So Rare As It Seems.

Oncologist. 2020 May 20;:

Authors: Lestuzzi C, Tratuferi L, Viel E, Buonadonna A, Vaccher E, Berretta M

PMID: 32436298 [PubMed - as supplied by publisher]

23 May 2020

13:37

Cardiotoxicity News

pubmed: tutte cardiotoxicity...

The efficiency of blackberry loaded AgNPs, AuNPs and Ag@AuNPs mediated pectin in the treatment of cisplatin-induced cardiotoxicity in experimental rats.

Int J Biol Macromol. 2020 May 19;:

Authors: Hussein J, El-Naggar ME, Fouda MMG, Morsy OM, Ajarem JS, Almalki AM, Allam AA, Mekawi EM