Blocking cardiac toxicity of anticancer drugs

阻断抗癌药物的心脏毒性

基本信息

批准号：
8666811
负责人：
MAHESH P GUPTA
金额：
$ 43.91万
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/8666811
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：Adrimycin（ADM）是针对癌症的最有效的化学治疗剂之一。尽管具有临床功效，该药物在治疗上与心脏的选择性毒性相关。 ADM治疗患者通常会出现延迟的心肌病和明显的充血性心力衰竭。在过去的十年中，已经做出了相当大的努力来开发一种可以阻止心脏毒性的疗法，但仍无法使用有效的治疗来打击建立ADM心肌病。心脏移植仍然是改善不可逆ADM心肌病患者存活的唯一明确解决方案。该药物毒性的基本机制尚未完全了解，但通常认为，涉及线粒体的活性氧（ROS）的产生增加。由于难以终止对癌症患者的ADM治疗，因此需要新的理解来定义引起这种药物毒性的潜在机制，并确定可用于保护心脏免受ADM心肌病的新治疗靶标。我的实验室对Sirtuins具有特定的兴趣，后者能够保护心脏免受Variou病理刺激的影响。最近，我们鉴定了一种SIRTUIN同工型SIRT3，可保护心肌细胞免受氧化应激介导的细胞死亡。 SIRT3缺乏的小鼠会发展与间质纤维化相关的心肌病，而具有心脏特异性SIRT3表达的转基因小鼠受到保护不受儿童儿茶酚胺诱导的心肌病和心力衰竭的保护。我们还发现，在ADM毒性期间，SIRT3水平大大降低，SIRT3的表达过度可保护心脏免受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规模乙酰化有关，并且可以通过SIRT3的过度表达来阻止这种作用。这些观察结果使我们假设SIRT3有可能保护心脏免受ADM介导的心脏损伤。因此，可以防止通过维持或升高由ADM治疗引起的细胞内SIRT3心肌病。我们将在以下三个目标中检验这一假设。（1）研究SIRT3激活是否可以阻止心肌细胞的ADM介导的死亡以及心脏成纤维细胞对肌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水平的药理学候选者是否有可能阻止心肌病，而不会损害药物的抗癌活性。这三个目标的成功结果将提高我们对导致心肌病的基本机制的理解，这可能指导我们制定新的治疗策略，以打击对心脏的抗癌药物的选择性毒性。