Blocking cardiac toxicity of anticancer drugs

阻断抗癌药物的心脏毒性

基本信息

批准号：
8422349
负责人：
MAHESH P GUPTA
金额：
$ 42.6万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8422349
关键词：
Acetylation Adipocytes Adriamycin PFS Adverse effects Anabolism Anthracycline Antibiotics Antineoplastic Agents Antioxidants Apoptosis Autophagocytosis Biogenesis Biological Process Cancer Patient Cardiac Cardiac Myocytes Cardiomyopathies Cardiotoxicity Catecholamines Cell Death Cells Cessation of life Congestive Heart Failure DNA Intercalation Data Deacetylation Development Dilated Cardiomyopathy Doxorubicin Drug toxicity Family Family member Fibroblasts Fibrosis Generations Goals Heart Heart Transplantation Heart failure Hematologic Neoplasms Human Injury Knock-out Knockout Mice Laboratories Link Longevity MAPK8 gene Malignant Neoplasms Mediating Metabolism Mitochondria Mitochondrial Proteins Molecular Weight Mus Myofibroblast Outcome Oxidative Stress Patients Pharmaceutical Preparations Production Protein Isoforms Protein Kinase Proteins Reactive Oxygen Species Sirtuins Solid Neoplasm Solutions Stimulus Stress Testing Topoisomerase II inhibition Toxic effect Transgenic Mice Transgenic Organisms Ventricular Function base cancer therapy cell growth chemotherapeutic agent clinical efficacy combat density design effective therapy fight against improved in vivo interest interstitial leukemia malignant breast neoplasm mammalian genome mitochondrial dysfunction neoplastic new therapeutic target novel therapeutics prevent protective effect public health relevance research study sarcoma soft tissue therapy development translational medicine tumor

项目摘要

DESCRIPTION (provided by applicant): Summary: Adriamycin (ADM) is one of the most effective chemotherapeutic agents used against verity of cancers. Despite its clinical efficacy, the drug is therapeutically associated wih selective toxicity to the heart. Patients with ADM therapy often develop delayed cardiomyopathy and overt congestive heart failure. In the past decade, considerable efforts have been made to develop a therapy which could block ADM cardio-toxicity, but still no effective therapy is available to combat an establish ADM cardiomyopathy. Cardiac transplantation remains the only definitive solution to improve survival of patients with irreversible ADM cardiomyopathy. The underlying mechanism of this drug toxicity is not yet fully understood, but it is generally believe that increased production of reactive oxygen species (ROS) from mitochondria is involved. Because discontinuation of ADM therapy for a cancer patient is difficult, new understanding is needed to define the underlying mechanism causing this drug toxicity, and to identify new therapeutic targets which could be used to protect the heart from ADM cardiomyopathy. My laboratory has specific interest in sirtuins, which are capable of protecting the heart from variou pathological stimuli. Recently, we identified a sirtuin isoform, SIRT3 which protects cardiomyocytes from oxidative stress-mediated cell death. SIRT3-deficent mice develop cardiomyopathy associated with interstitial fibrosis, and transgenic mice with cardiac-specific over expression of SIRT3 are protected from developing catecholamine-induced cardiomyopathy and heart failure. We also found that SIRT3 levels are significantly reduced during ADM cardio-toxicity, and over expression of SIRT3 protects hearts from ADM-mediated loss of cardiac function. Furthermore, our preliminary data show that ADM-cardio-toxicity is associated with massive acetylation of mitochondrial proteins, and that this effect can be blocked by over expression of SIRT3. These observations led us to hypothesize that SIRT3 has the potential to protect the heart from ADM mediated cardiac injury. Therefore, by maintaining or elevating intracellular levels of SIRT3 cardiomyopathy resulting from ADM therapy can be prevented. We will test this hypothesis in the following three aims. (1) Study whether SIRT3 activation can block ADM-mediated death of cardiomyocytes and differentiation of cardiac fibroblasts to myofibroblasts and the development of cardiomyopathy in mice. (2) Determine the underlying mechanisms through which SIRT3 protects the heart from ADM-mediated cardiomyopathy. (3) Study whether pharmacological candidates capable of activating endogenous SIRT3 levels hold the potential to block ADM cardiomyopathy without compromising anti-cancer activity of the drug. A successful outcome of these three aims will advance our understanding of the basic mechanism causing ADM cardiomyopathy, and that this may guide us to develop new therapeutic strategies to combating selective toxicity of anti- cancer drugs to the heart.

描述（由申请人提供）：摘要：阿霉素 (ADM) 是对抗癌症最有效的化疗药物之一。尽管具有临床功效，但该药物在治疗上与对心脏的选择性毒性相关。接受 ADM 治疗的患者经常出现迟发性心肌病和明显的充血性心力衰竭。在过去的十年中，人们付出了相当大的努力来开发一种可以阻断 ADM 心脏毒性的疗法，但仍然没有有效的疗法来对抗已确定的 ADM 心肌病。心脏移植仍然是提高不可逆 ADM 心肌病患者生存率的唯一最终解决方案。这种药物毒性的潜在机制尚不完全清楚，但普遍认为与线粒体活性氧 (ROS) 产生的增加有关。由于癌症患者很难停止 ADM 治疗，因此需要新的认识来确定导致该药物毒性的潜在机制，并确定可用于保护心脏免受 ADM 心肌病影响的新治疗靶点。我的实验室对去乙酰化酶特别感兴趣，它能够保护心脏免受各种病理刺激。最近，我们发现了一种沉默调节蛋白异构体 SIRT3，它可以保护心肌细胞免受氧化应激介导的细胞死亡。 SIRT3缺陷的小鼠会患上与间质纤维化相关的心肌病，而心脏特异性过度表达SIRT3的转基因小鼠则不会患上儿茶酚胺诱导的心肌病和心力衰竭。我们还发现，ADM 心脏毒性期间 SIRT3 水平显着降低，并且 SIRT3 的过度表达可以保护心脏免受 ADM 介导的心脏功能丧失。此外，我们的初步数据表明，ADM 心脏毒性与线粒体蛋白的大量乙酰化有关，并且这种效应可以通过 SIRT3 的过度表达来阻断。这些观察结果使我们推测 SIRT3 有可能保护心脏免受 ADM 介导的心脏损伤。因此，通过维持或升高SIRT3的细胞内水平，可以预防由ADM治疗引起的心肌病。我们将在以下三个目标中检验这一假设。 (1)研究SIRT3激活是否可以阻断ADM介导的心肌细胞死亡和心肌成纤维细胞向肌成纤维细胞的分化以及小鼠心肌病的发展。 (2) 确定 SIRT3 保护心脏免受 ADM 介导的心肌病的潜在机制。 (3) 研究能够激活内源性 SIRT3 水平的候选药物是否具有阻断 ADM 心肌病而不损害药物抗癌活性的潜力。这三个目标的成功实现将促进我们对引起 ADM 心肌病的基本机制的理解，并且这可能指导我们开发新的治疗策略来对抗抗癌药物对心脏的选择性毒性。