Atypical G Protein β5 Promotes Cardiac Oxidative Stress, Apoptosis, and Fibrotic Remodeling in Response to Multiple Cancer Chemotherapeutics.
TL;DR: The experiments suggest that inhibition of Gβ5 might represent a novel means to circumvent cardiotoxicity in cancer patients whose treatment regimens include anthracyclines, taxanes, or fluoropyrimidines.
Abstract: The clinical use of multiple classes of cancer chemotherapeutics is limited by irreversible, dose-dependent, and sometimes life-threatening cardiotoxicity. Though distinct in their mechanisms of action, doxorubicin, paclitaxel, and 5-FU all induce rapid and robust upregulation of atypical G protein Gβ5 in the myocardium correlating with oxidative stress, myocyte apoptosis, and the accumulation of proinflammatory and profibrotic cytokines. In ventricular cardiac myocytes (VCM), Gβ5 deficiency provided substantial protection against the cytotoxic actions of chemotherapeutics, including reductions in oxidative stress and simultaneous attenuation of ROS-dependent activation of the ATM and CaMKII proapoptotic signaling cascades. In addition, Gβ5 loss allowed for maintenance of Δψm, basal mitochondrial calcium uniporter expression, and mitochondrial Ca2+ levels, effects likely to preserve functional myocyte excitation-contraction coupling. The deleterious effects of Gβ5 are not restricted to VCM, however, as Gβ5 knockdown also reduces chemotherapy-induced release of proinflammatory cytokines (e.g., TNFα), hypertrophic factors (e.g., ANP), and profibrotic factors (e.g., TGFβ1) from both VCM and ventricular cardiac fibroblasts, with the most dramatic reduction occurring in cocultured cells. Our experiments suggest that Gβ5 facilitates the myofibroblast transition, the persistence of which contributes to pathologic remodeling and heart failure. The convergence of Gβ5-mediated, ROS-dependent signaling pathways in both cell types represents a critical etiological factor in the pathogenesis of chemotherapy-induced cardiotoxicity. Indeed, intracardiac injection of Gβ5-targeted shRNA allowed for heart-specific protection against the damaging impact of chronic chemotherapy. Together, our results suggest that inhibition of Gβ5 might represent a novel means to circumvent cardiotoxicity in cancer patients whose treatment regimens include anthracyclines, taxanes, or fluoropyrimidines.Significance: These findings suggest that inhibiting an atypical G-protein might provide a strategy to limit the cardiotoxicity in cancer patients treated with anthracyclines, taxanes, or fluoropyrimidines. Cancer Res; 78(2); 528-41. ©2017 AACR.
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TL;DR: Current knowledge on the role of the mitochondrial calcium uniporter (MCU) complex in multiple cancer types and models is reviewed and a perspective for future research and clinical considerations is provided.
Abstract: The important role of mitochondria in cancer biology is gaining momentum. With their regulation of cell survival, metabolism, basic cell building blocks, and immunity, among other functions, mitochondria affect not only cancer progression but also the response and resistance to current treatments. Calcium ions are constantly shuttled in and out of mitochondria; thus, playing an important role in the regulation of various cellular processes. The mitochondrial calcium uniporter (MCU) channel and its associated regulators transport calcium across the inner mitochondrial membrane to the mitochondrial matrix. Due to this central role and the capacity to affect cell behavior and fate, the MCU complex is being investigated in different cancers and cancer-related conditions. Here, we review current knowledge on the role of the MCU complex in multiple cancer types and models; we also provide a perspective for future research and clinical considerations.
77 citations
Cites background from "Atypical G Protein β5 Promotes Card..."
...Cardiotoxicity in cancer patients Inhibition of Gβ5 could prevent cardiotoxicity in cancer patients treated with anthracyclines, taxanes, or fluoropyrimidines Gβ5-loss maintains membrane potential, basal MCU expression, and mCa levels, allowing functional myocyte activity [14]...
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TL;DR: It is suggested that melatonin treatment attenuated doxorubicin‐induced cardiotoxicity through preserving YAP levels, which in turn decreases oxidative stress and apoptosis.
Abstract: There are increasing concerns related to the cardiotoxicity of doxorubicin in the clinical setting. Recently, melatonin has been shown to exert a cardioprotective effect in various cardiovascular diseases, including cardiotoxic conditions. In this study, we examined the possible protective effects of melatonin on doxorubicin-induced cardiotoxicity and explored the underlying mechanisms related to this process. We found that in vitro doxorubicin treatment significantly decreased H9c2 cell viability and induced apoptosis as manifested by increased TUNEL-positive cells, down-regulation of anti-apoptotic protein Bcl-2, as well as up-regulation of pro-apoptotic protein Bax. This was associated with increased reactive oxygen species (ROS) levels and decreased mitochondrial membrane potentials (MMP). In vivo, five weeks of doxorubicin treatment significantly decreased cardiac function, as evaluated by echocardiography. TUNEL staining results confirmed the increased apoptosis caused by doxorubicin. On the other hand, combinational treatment of doxorubicin with melatonin decreased cardiomyocyte ROS and apoptosis levels, along with increasing MMP. Such doxorubicin-melatonin co-treatment alleviated in vivo doxorubicin-induced cardiac injury. Western Blots, along with in vitro immunofluorescence and in vivo immunohistochemical staining confirmed that doxorubicin treatment significantly down-regulated Yes-associated protein (YAP) expression, while YAP levels were maintained under co-treatment of doxorubicin and melatonin. YAP inhibition by siRNA abolished the protective effects of melatonin on doxorubicin-treated cardiomyocytes, with reversed ROS level and apoptosis. Our findings suggested that melatonin treatment attenuated doxorubicin-induced cardiotoxicity through preserving YAP levels, which in turn decreases oxidative stress and apoptosis.
23 citations
TL;DR: In this paper, the role of ROS mediated oxidative stress mediated by oncological treatments in inducing cardiovascular disease was discussed and strategies that potentially counteract the oxidative stress in order to fight the onset and progression of cardiovascular disease.
Abstract: Reactive oxygen species (ROS) are molecules involved in signal transduction pathways with both beneficial and detrimental effects on human cells ROS are generated by many cellular processes including mitochondrial respiration, metabolism and enzymatic activities In physiological conditions, ROS levels are well-balanced by antioxidative detoxification systems In contrast, in pathological conditions such as cardiovascular, neurological and cancer diseases, ROS production exceeds the antioxidative detoxification capacity of cells, leading to cellular damages and death In this review, we will first describe the biology and mechanisms of ROS mediated oxidative stress in cardiovascular disease Second, we will review the role of oxidative stress mediated by oncological treatments in inducing cardiovascular disease Lastly, we will discuss the strategies that potentially counteract the oxidative stress in order to fight the onset and progression of cardiovascular disease, including that induced by oncological treatments
21 citations
TL;DR: In conclusion, polydatin effectively inhibited hypoxia- and AMI-induced myocardial damage by promotion of Nrf2/HO-1 signaling.
Abstract: Polydatin is a traditional Chinese medicine that provides myocardial protection after acute myocardial infarction (AMI) The study aim was to investigate the myocardial protection polydatin in H9c2 myocardial cells cultured in a hypoxic atmosphere and in a rat AMI model induced by ligating the left anterior descending coronary artery and treated with polydatin 100 mg/kg/day for 30 days The involvement of Nrf2 in mediating the effects of polydatin was investigated in H9c2 cells following Nrf2 knockdown by transfection of siRNA Polydatin suppressed hypoxia-induced H9c2 cell apoptosis and reactive oxygen species (ROS) generation by promoting Nrf2/HO-1 signaling Nrf2 knockdown reversed the protective effects of polydatin against hypoxia-induced myocardial cell injury The in vivo results were consistent with polydatin suppression of apoptosis and ROS generation in myocardial tissue by promotion of Nrf2/HO-1 signaling In conclusion, polydatin effectively inhibited hypoxia- and AMI-induced myocardial damage by promotion of Nrf2/HO-1 signaling
21 citations
TL;DR: The beneficial effects of QL on DOX-induced CHF in rats are mediated by reduction in myocardial fibrosis, promotion of TGF-β3/Smad7, and inhibition of T GF-β1/ Smad3, which may also modulate specific miRNAs.
Abstract: Context: Therapeutic doxorubicin administration is restricted as this anticancer drug may be cardiotoxic. The traditional Chinese medicine qiliqiangxin has been approved for clinical treatment of c...
17 citations
Cites background from "Atypical G Protein β5 Promotes Card..."
...Of these, cardiomyocyte inflammation and fibrosis are ordinary pathological mechanisms of myocardial remodelling in DOX-induced CHF (Liu et al. 2016; Chakraborti et al. 2018)....
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...Cardiac extracellular matrix remodelling is an important mechanism of left ventricular dysfunction and adverse outcome after DOX treatment (Liu et al. 2016; Shabalala et al. 2017; Zhang et al. 2017; Chakraborti et al. 2018)....
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...However, its clinical use is severely limited by its side effects including cardiotoxicity, cardiac remodelling, and chronic heart failure (Lipshultz et al. 2012; Liu et al. 2016; Shabalala et al. 2017; Zhang et al. 2017; Chakraborti et al. 2018)....
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References
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TL;DR: In this article, the authors reviewed commonly used chemotherapy agents, including several recently approved medications, for their propensity to cause cardiotoxicity and developed management plans, as well as strategies to reduce cardiotoxic effects.
Abstract: The cardiotoxicity of anticancer agents can lead to significant complications that can affect patients being treated for various malignancies. The severity of such toxicity depends on many factors such as the molecular site of action, the immediate and cumulative dose, the method of administration, the presence of any underlying cardiac condition, and the demographics of the patient. Moreover, toxicity can be affected by current or previous treatment with other antineoplastic agents. Cardiotoxic effects can occur immediately during administration of the drug, or they may not manifest themselves until months or years after the patient has been treated. In this article we review commonly used chemotherapy agents, including several recently approved medications, for their propensity to cause cardiotoxicity. Further research will be required to more accurately predict which patients are at risk for developing cardiotoxicity. In addition, management plans, as well as strategies to reduce cardiotoxicity, need to be developed.
792 citations
"Atypical G Protein β5 Promotes Card..." refers background in this paper
...Anti-microtubule agents such as paclitaxel, in contrast, are associated with dysregulations of the cardiac conduction system including sinus bradycardia, atrioventricular block, and ventricular tachycardia, in addition to chronic congestive heart failure(3)....
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...Anthracyclines, including the widely used drug doxorubicin, induce dilated or restrictive cardiomyopathy, left ventricular dysfunction and congestive heart failure(3)....
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TL;DR: The potential cardiovascular toxicities for a range of cancer chemotherapeutic and chemopreventive agents are summarized and the importance of evaluating cardiovascular risk when patients enter into trials is emphasized and the need to develop guidelines that include collateral effects on the cardiovascular system is emphasized.
Abstract: Due to the aging of the populations of developed countries and a common occurrence of risk factors, it is increasingly probable that a patient may have both cancer and cardiovascular disease. In addition, cytotoxic agents and targeted therapies used to treat cancer, including classic chemotherapeutic agents, monoclonal antibodies that target tyrosine kinase receptors, small molecule tyrosine kinase inhibitors, and even antiangiogenic drugs and chemoprevention agents such as cyclooxygenase-2 inhibitors, all affect the cardiovascular system. One of the reasons is that many agents reach targets in the microenvironment and do not affect only the tumor. Combination therapy often amplifies cardiotoxicity, and radiotherapy can also cause heart problems, particularly when combined with chemotherapy. In the past, cardiotoxic risk was less evident, but it is increasingly an issue, particularly with combination therapy and adjuvant therapy. Today's oncologists must be fully aware of cardiovascular risks to avoid or prevent adverse cardiovascular effects, and cardiologists must now be ready to assist oncologists by performing evaluations relevant to the choice of therapy. There is a need for cooperation between these two areas and for the development of a novel discipline, which could be termed cardio-oncology or onco-cardiology. Here, we summarize the potential cardiovascular toxicities for a range of cancer chemotherapeutic and chemopreventive agents and emphasize the importance of evaluating cardiovascular risk when patients enter into trials and the need to develop guidelines that include collateral effects on the cardiovascular system. We also discuss mechanistic pathways and describe several potential protective agents that could be administered to patients with occult or overt risk for cardiovascular complications.
678 citations
"Atypical G Protein β5 Promotes Card..." refers background in this paper
...Despite their proven capacity to improve long-term cancer patient survival(1), the utility of anthracycline, taxane and fluoropyrimidine chemotherapeutics is limited by irreversible cardiac toxicity(2)....
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...Though proven to improve patient survival over a 20-year period(1), the utility of many chemotherapeutics including anthracyclines, taxanes, and fluoropyrimidines is limited by adverse effects amongst them dose-dependent and often irreversible cardiac damage that can result in eventual heart failure(2)....
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TL;DR: It is found that cardiotoxicity develops through the preferential accumulation of iron inside the mitochondria following doxorubicin treatment, and that reducing mitochondrial iron levels protects against doxorbicin-induced cardiomyopathy.
Abstract: Doxorubicin is an effective anticancer drug with known cardiotoxic side effects. It has been hypothesized that doxorubicin-dependent cardiotoxicity occurs through ROS production and possibly cellular iron accumulation. Here, we found that cardiotoxicity develops through the preferential accumulation of iron inside the mitochondria following doxorubicin treatment. In isolated cardiomyocytes, doxorubicin became concentrated in the mitochondria and increased both mitochondrial iron and cellular ROS levels. Overexpression of ABCB8, a mitochondrial protein that facilitates iron export, in vitro and in the hearts of transgenic mice decreased mitochondrial iron and cellular ROS and protected against doxorubicin-induced cardiomyopathy. Dexrazoxane, a drug that attenuates doxorubicin-induced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicin-induced cardiac damage. Finally, hearts from patients with doxorubicin-induced cardiomyopathy had markedly higher mitochondrial iron levels than hearts from patients with other types of cardiomyopathies or normal cardiac function. These results suggest that the cardiotoxic effects of doxorubicin develop from mitochondrial iron accumulation and that reducing mitochondrial iron levels protects against doxorubicin-induced cardiomyopathy.
652 citations
"Atypical G Protein β5 Promotes Card..." refers background in this paper
...following doxorubicin exposure through dysregulation of the mitochondrial electron transport chain(8,9), direct interaction with endothelial nitric oxide synthase (eNOS)(10), and activation of NADPH oxidase (Nox) complexes(11,12)....
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TL;DR: relevant cellular, subcellular, and molecular mechanisms integral to cardiac fibrosis and consequent remodelling of atria and ventricles with a heterogeneity in cardiomyocyte size are reviewed.
Abstract: The syncytium of cardiomyocytes in the heart is tethered within a matrix composed principally of type I fibrillar collagen The matrix has diverse mechanical functions that ensure the optimal contractile efficiency of this muscular pump In the diseased heart, cardiomyocytes are lost to necrotic cell death, and phenotypically transformed fibroblast-like cells-termed 'myofibroblasts'-are activated to initiate a 'reparative' fibrosis The structural integrity of the myocardium is preserved by this scar tissue, although at the expense of its remodelled architecture, which has increased tissue stiffness and propensity to arrhythmias A persisting population of activated myofibroblasts turns this fibrous tissue into a living 'secretome' that generates angiotensin II and its type 1 receptor, and fibrogenic growth factors (such as transforming growth factor-β), all of which collectively act as a signal-transducer-effector signalling pathway to type I collagen synthesis and, therefore, fibrosis Persistent myofibroblasts, and the resultant fibrous tissue they produce, cause progressive adverse myocardial remodelling, a pathological hallmark of the failing heart irrespective of its etiologic origin Herein, we review relevant cellular, subcellular, and molecular mechanisms integral to cardiac fibrosis and consequent remodelling of atria and ventricles with a heterogeneity in cardiomyocyte size Signalling pathways that antagonize collagen fibrillogenesis provide novel strategies for cardioprotection
538 citations
"Atypical G Protein β5 Promotes Card..." refers background in this paper
...Though necessary to maintain structural integrity following cell loss, the persistence of these secretory factors causes progressive, pathological remodeling, a hallmark of the failing heart(45)....
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TL;DR: This study is the first, to the authors' knowledge, to establish a relationship between the radiation dose received by the heart during radiotherapy for a childhood cancer and long-term cardiac mortality and a significant excess risk of cardiac mortality associated with a high cumulative dose of anthracyclines.
Abstract: Purpose The purpose of this study was to assess the role of treatment in long-term overall and cardiovascular mortality after childhood cancer. Patients and Methods We studied 4,122 5-year survivors of a childhood cancer diagnosed before 1986 in France and the United Kingdom. Information on chemotherapy was collected, and the radiation dose delivered to the heart was estimated for 2,870 patients who had received radiotherapy. Results After 86,453 person-years of follow-up (average, 27 years), 603 deaths had occurred. The overall standardized mortality ratio (SMR) was 8.3-fold higher (95% CI, 7.6-fold to 9.0-fold higher) in relation to the general populations in France and the United Kingdom. Thirty-two patients had died as a result of cardiovascular diseases (ie, 5.0-fold [95% CI, 3.3-fold to 6.7-fold] more than expected). The risk of dying as a result of cardiac diseases (n = 21) was significantly higher in individuals who had received a cumulative anthracycline dose greater than 360 mg/m2 (relative risk...
381 citations
"Atypical G Protein β5 Promotes Card..." refers background in this paper
...Indeed, the risk of cardiac death in childhood cancer survivors receiving high dose anthracycline chemotherapy is increased 4 fold(4)....
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