Blocking cardiac toxicity of anticancer drugs

描述（由申请人提供）： 阿霉素（ADM）是目前治疗多种恶性肿瘤最有效的化疗药物之一。尽管其临床疗效，但该药物在治疗上与对心脏的选择性毒性相关。ADM治疗的患者经常发展为迟发性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可以阻断ADM心脏毒性的疗法，但是仍然没有有效的疗法可以对抗已建立的ADM心肌病。心脏移植仍然是提高不可逆ADM心肌病患者生存率的唯一决定性解决方案。这种药物毒性的潜在机制尚未完全了解，但通常认为与线粒体活性氧（ROS）的产生增加有关。由于癌症患者的ADM治疗很难中断，因此需要新的理解来定义导致这种药物毒性的潜在机制，并确定可用于保护心脏免受ADM心肌病的新治疗靶点。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。最近，我们鉴定了sirtuin亚型SIRT3，其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，而心脏特异性过表达SIRT3的转基因小鼠被保护免于发生儿茶酚胺诱导的心肌病和心力衰竭。我们还发现，在ADM心脏毒性期间，SIRT3水平显著降低，并且SIRT3的过表达保护心脏免受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，并且这种作用可以通过SIRT3的过度表达来阻断。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，通过维持或升高细胞内SIRT 3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激活是否可以阻断ADM介导的心肌细胞死亡和心脏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水平的药理学候选物是否具有阻断ADM心肌病而不损害药物抗癌活性的潜力。这三个目标的成功结果将促进我们对ADM心肌病的基本机制的理解，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。

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.