Neutral sphingomyelinase-2 as a mediator of Doxorubicin-induced cardiotoxicity

中性鞘磷脂酶 2 作为阿霉素诱导心脏毒性的介质

• 批准号: 10348201
• 负责人: Christopher James Clarke
• 金额: $ 35.45万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10348201
• 关键词: Adverse effects; Anthracycline; Apoptosis; Binding; Biological Markers; Breast Cancer Model; Cardiac; Cardiac Myocytes; Cardiotonic Agents; Cardiotoxicity; Cardiovascular system; Cell Death; Cells; Ceramides; Cessation of life; Chronic; Clinical; DNA Damage; Data; Development; Dexrazoxane; Doxorubicin; Enzymes; Exposure to; FDA approved; Generations; Goals; Heart; Heart Injuries; Image; In Vitro; Intervention; Laboratories; Malignant Neoplasms; Mediating; Mediator of activation protein; Metabolism; Myocardial dysfunction; Neoplasm Metastasis; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Prevention; Publishing; Regulation; Research; Role; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sphingolipids; Sphingomyelinase; Survival Rate; TP53 gene; Testing; Therapeutic; Tissues; Topoisomerase; Toxic effect; Treatment Efficacy; Work; Xenograft Model; anti-cancer; anticancer activity; antitumor effect; base; biological adaptation to stress; cancer survival; cancer therapy; cardioprotection; cellular targeting; chemotherapy; clinical efficacy; coronary fibrosis; design; druggable target; early onset; heart damage; improved; in vivo; inhibitor; insight; interest; loss of function; malignant breast neoplasm; new therapeutic target; novel; novel therapeutics; promoter; response; side effect; translational potential; tumor; tumor growth

ABSTRACT Doxorubicin (Dox) is a mainstay in the treatment of many cancers yet its utility is limited by cardiovascular toxicity. While multiple mechanisms underlying this cardiotoxicity have been proposed, strategies targeting these pathways have had marginal effects or interfere with anti-cancer effects of the drug. Such concerns have restricted the clinical use of dexrazoxane which is currently the only FDA-approved cardio-protective agent. As cancer survival rates improve and more patients are exposed to Dox, there is a critical need for new strategies to mitigate the cardiotoxicity without comprising its therapeutic efficacy. Bioactive sphingolipids (SLs), especially ceramide (Cer), are well-established mediators of the chemotherapy stress response across diverse cancers. While this increased interest in targeting SL metabolism to enhance chemotherapy responses, targeting SL metabolism to reduce chemotoxicities is largely unexplored. We recently identified the Cer-generating enzyme neutral sphingomyelinase-2 (nSMase2) as a primary Dox-regulated SL enzyme in breast cancer. Here, our preliminary studies begin to implicate nSMase2-derived Cer in the Dox-induced DNA damage response of cardiomyocytes (CMs) and show that in vivo loss of nSMase2 activity protects from the onset of Dox-induced cardiac dysfunction and damage. Crucially, nSMase2 appears to be dispensable for the in vitro and in vivo anti- cancer effects of Dox on breast cancer. Based on these data, the central hypothesis is that the nSMase2- ceramide pathway is essential for Dox-induced cardiotoxicity but dispensable for Dox-induced anti-cancer activity. We propose three specific aims: The first aim will establish Dox-induced activation of the nSMase2- Cer pathway in cardiac cells and tissues combining in vitro and in vivo approaches to establish nSMase2 induction in CMs as a major pathway of Dox-induced Cer generation in the heart. The second aim will define the role of the nSMase2-Cer pathway in mediating Dox-induced cardiotoxicity using in vitro and in vivo loss of function approaches to establish nSMase2 in CMs as a mediator of Dox-induced CM cell death and cardiac fibrosis. The third aim will establish the therapeutic potential of nSMase2 inhibitors as cardioprotective agents that do not interfere with the anti-cancer activity of Dox using syngeneic xenograft models of breast cancer to demonstrate the efficacy of nSMase2 inhibitors as cardioprotective agents that do not interfere with Dox reduction of tumor growth and metastasis. Overall, these studies will provide novel insight into the pathogenesis of Dox-induced cardiotoxicity and establish nSMase2 as a novel druggable target for cardioprotection. This will provide a rational basis for the development of nSMase2 inhibitors as novel cardioprotective agents.

摘要 阿霉素（Dox）是治疗许多癌症的主要药物，但其效用受到心血管毒性的限制。 虽然已经提出了这种心脏毒性的多种机制，但针对这些机制的策略 途径具有边际效应或干扰药物的抗癌作用。这种关切 限制了右雷佐生的临床使用，右雷佐生是目前FDA批准的唯一心脏保护剂。作为 癌症存活率提高，更多的患者暴露于Dox，迫切需要新的策略 以减轻心脏毒性而不影响其治疗效果。生物活性鞘脂（SL），特别是 神经酰胺（Cer）是各种癌症中化疗应激反应的公认介质。 虽然这增加了靶向SL代谢以增强化疗反应的兴趣，但靶向SL代谢的研究仍然存在。 降低化学毒性的代谢在很大程度上未被探索。我们最近发现了一种能产生铈的酶 中性鞘磷脂酶-2（nSMase 2）作为乳腺癌中主要的Dox调节的SL酶。这里我们的 初步研究开始暗示nSMase 2衍生的Cer参与Dox诱导的DNA损伤反应， 心肌细胞（CM），并显示在体内nSMase 2活性的损失保护免受Dox诱导的心肌细胞（CM）的发病。 心脏功能障碍和损伤。重要的是，nSMase 2似乎是体外和体内抗- Dox对乳腺癌的影响基于这些数据，中心假设是nSM酶2- 神经酰胺通路在Dox的心脏毒性中起重要作用，但在Dox的抗癌作用中起重要作用 活动我们提出了三个具体的目标：第一个目标是建立Dox诱导的nSMase 2 - 1激活。 心肌细胞和组织中的Cer通路结合体内外方法建立nSMase 2 CM中的诱导作为心脏中Dox诱导的Cer产生的主要途径。第二个目标将定义 使用体外和体内损失研究nSMase 2-Cer通路在介导Dox诱导的心脏毒性中的作用 在CM中建立nSMase 2作为Dox诱导的CM细胞死亡和心脏病的介导剂的功能方法 纤维化第三个目的是确定nSMase 2抑制剂作为心脏保护剂的治疗潜力。 不干扰Dox抗癌活性的药物，使用乳腺癌的同基因异种移植模型 证明nSMase 2抑制剂作为心脏保护剂的疗效， Dox减少肿瘤生长和转移。总的来说，这些研究将提供新的见解， Dox诱导的心脏毒性的发病机制，并建立nSMase 2作为一种新的药物靶点， 心脏保护这将为nSMase 2抑制剂的开发提供合理的基础 心脏保护剂。