Blocking cardiac toxicity of anticancer drugs

阻断抗癌药物的心脏毒性

• 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
• 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

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)是目前治疗多种癌症最有效的化疗药物之一。尽管临床有效，但这种药物在治疗上与心脏的选择性毒性有关。使用ADM治疗的患者通常会出现迟发性心肌病和明显的充血性心力衰竭。在过去的十年里，人们已经做出了相当大的努力来开发一种可以阻断ADM心脏毒性的治疗方法，但仍然没有有效的治疗方法来对抗已建立的ADM心肌病。心脏移植仍然是提高不可逆ADM心肌病患者存活率的唯一确定的解决方案。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产生的活性氧物种(ROS)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定义导致这种药物毒性的潜在机制，并确定新的治疗靶点，以保护心脏免受ADM心肌病的影响。我的实验室对sirtuins特别感兴趣，它能够保护心脏免受各种病理刺激的影响。最近，我们发现了一种sirtuin亚型，SIRT3，它可以保护心肌细胞免受氧化应激介导的细胞死亡。SIRT3缺陷小鼠发生与间质纤维化相关的心肌病，心脏特异性过表达SIRT3的转基因小鼠可以预防儿茶酚胺诱导的心肌病和心力衰竭。我们还发现，在ADM心脏毒性过程中，SIRT3水平显著降低，过表达SIRT3可以保护心脏免受ADM介导的心功能丧失的影响。此外，我们的初步数据表明，ADM的心脏毒性与线粒体蛋白的大量乙酰化有关，这种作用可以被SIRT3的过度表达所阻断。这些观察结果使我们假设SIRT3具有保护心脏免受ADM介导的心脏损伤的潜力。因此，通过维持或提高细胞内SIRT3水平可以预防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激活能否阻断ADM介导的小鼠心肌细胞死亡、心肌成纤维细胞向肌成纤维细胞的分化及心肌病的发生发展。(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在不影响药物抗癌活性的情况下阻断ADM心肌病的潜力。这三个目标的成功实现将促进我们对ADM心肌病基本机制的理解，并可能指导我们开发新的治疗策略，以对抗抗癌药物对心脏的选择性毒性。