Mechanisms of cardiac chemosensitivity

心脏化疗敏感性的机制

• 批准号: 10002633
• 负责人: Zhaokang Cheng
• 金额: $ 44.91万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002633
• 关键词: Ablation; Adolescent; Adriamycin PFS; Adult; Age; Anthracyclines; Antineoplastic Agents; Apoptosis; Apoptotic; BIM Bcl-2-binding protein; Biological Assay; CDK2 gene; Cancer Control; Cancer Patient; Cancer Survivor; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Cause of Death; Cell Cycle; Cell Cycle Arrest; Cell Death; Cessation of life; Child; Cyclin-Dependent Kinase Inhibitor; Cytotoxic Chemotherapy; DNA biosynthesis; Data; Dissociation; Doxorubicin; FOXO1A gene; Family; Foundations; G1 Phase; G1/S Transition; Genes; Genetic Transcription; Growth; Heart; In Vitro; Injury; Iron; Lead; Malignant Neoplasms; Mediating; Mediator of activation protein; Mitochondria; Modernization; Molecular; Morbidity - disease rate; Muscle Cells; Myocardial; Myocardial dysfunction; Names; Pathogenesis; Pathway interactions; Patients; Preventive; RBL2 gene; Regulation; Reporter; Repression; Resistance; Retinoblastoma Protein; Risk; Risk Factors; Role; S Phase; System; Testing; Therapeutic; Tissues; Topoisomerase; Treatment-Related Cancer; United States; Work; age group; base; cancer diagnosis; cancer therapy; cardiogenesis; cardioprotection; chemotherapy; chromatin immunoprecipitation; experimental study; gain of function; heart damage; high risk; in vivo; insight; mortality; novel; overexpression; patient population; prevent; pro-apoptotic protein; response; screening; side effect; transcription factor; treatment strategy

PROJECT SUMMARY Advances in cancer diagnosis and therapeutics over the last three decades have greatly reduced cancer mortality rates. However, this benefit was accompanied by a paradoxical rise of treatment-related cardiotoxicity, which has become the most common non-cancer cause of death among the 15.5 million cancer survivors in the United States. The most severe form of cardiotoxicity is Type I cardiotoxicity, which is predominantly caused by the anthracycline family of anticancer agents including doxorubicin (DOX, trade name: Adriamycin) due to induction of myocyte death. Younger age at treatment is a major risk factor for developing anthracycline cardiotoxicity. Most recent findings suggested that chemosensitivity in young tissues was caused by higher levels of apoptosis in response to cytotoxic chemotherapies. A key feature distinguishing children from adults is that the heart is still growing with active DNA synthesis and significant cell cycle activity. We hypothesize that elevated cell cycle activity in cardiomyocytes enhances cardiac chemosensitivity by accelerating apoptosis following DOX exposure. In support of this hypothesis, we have shown that expression of p21, a Cip/Kip family cyclin-dependent kinase (CDK) inhibitor that arrests the cell cycle, protected against DOX-induced apoptotic death of cardiomyocytes. By contrast, activation of CDK2 exacerbated DOX-induced cardiomyocyte apoptosis and promoted expression of the pro-apoptotic protein Bim. Importantly, DOX treatment induced CDK2 activation in vitro and in vivo, suggesting that CDK2 activation may represent a key mechanism underlying DOX-induced myocyte apoptosis and cardiotoxicity. Based on these findings, we propose to further tackle the role of cell cycle machinery in cardiomyocyte apoptosis and cardiac chemosensitivity by pursuing the following three Specific Aims: 1) Define the mechanisms of CDK2-mediated DOX cardiotoxicity; 2) Investigate the regulation of CDK2 activity in cardiomyocytes; 3) Identify the common regulator for cell cycle activity and cardiac chemosensitivity. The proposed studies will have the potential to uncover novel mechanisms underlying cardiac chemosensitivity, and may lay the foundation for developing new treatment strategies against anthracycline cardiomyopathy.

项目摘要 在过去的三十年里，癌症诊断和治疗的进步大大减少了癌症 死亡率。然而，这种益处伴随着治疗相关心脏毒性的矛盾上升， 它已成为美国1550万癌症幸存者中最常见的非癌症死亡原因。 美国的心脏毒性的最严重形式是I型心脏毒性，其主要由以下引起： 蒽环类抗癌剂，包括阿霉素（DOX，商品名：Adriamycin），由于 诱导肌细胞死亡。 治疗时年龄较小是发生蒽环类药物心脏毒性的主要危险因素。最新调查结果 表明年轻组织的化学敏感性是由响应于细胞凋亡的较高水平引起的 细胞毒性化疗。儿童区别于成人的一个关键特征是心脏仍在生长， 活跃的DNA合成和显著的细胞周期活性。我们假设，在细胞周期中， 心肌细胞通过加速DOX暴露后的细胞凋亡来增强心脏化学敏感性。在 为支持这一假设，我们已经证明了Cip/Kip家族细胞周期蛋白依赖性激酶p21表达 (CDK)抑制剂，阻止细胞周期，保护免受DOX诱导的心肌细胞凋亡。通过 相反，CDK 2的激活加剧了DOX诱导的心肌细胞凋亡，并促进了 促凋亡蛋白Bim.重要的是，DOX处理在体外和体内诱导CDK 2活化， 提示CDK 2激活可能是DOX诱导心肌细胞凋亡的关键机制 和心脏毒性。基于这些发现，我们建议进一步解决细胞周期机制在 心肌细胞凋亡和心脏化疗敏感性的研究，其具体目标如下：1）定义 CDK 2介导DOX心脏毒性的机制; 2）研究CDK 2活性在DOX心脏毒性中的调节作用。 3）确定细胞周期活性和心脏化学敏感性的共同调节因子。的 拟议的研究将有可能揭示心脏化学敏感性的新机制， 可能为开发蒽环类药物心肌病的新治疗策略奠定基础。