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

基本信息

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
项目类别：
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

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

展开

项目摘要

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.

抽象的阿霉素（DOX）是许多癌症治疗的中流型，但其效用受心血管毒性的限制。尽管已经提出了这种心脏毒性的多种机制，但针对这些的策略途径具有边际作用或干扰该药物的抗癌作用。这样的担忧限制了右旋唑烷的临床使用，这是目前唯一经FDA批准的心脏保护剂。作为癌症存活率提高了，更多的患者暴露于DOX，对新策略的需求迫切为了减轻心脏毒性而不包含其治疗功效。生物活性鞘脂（SLS），尤其是神经酰胺（CER）是各种癌症中化学疗法应激反应的良好介质。尽管这种对靶向SL代谢以增强化学疗法反应的兴趣增加了，但针对SL 降低趋化性的代谢在很大程度上没有探索。我们最近确定了生成的酶中性鞘磷脂酶-2（NSMASE2）是乳腺癌中原发性DOX调节的SL酶。在这里，我们的初步研究开始在DOX诱导的DNA损伤响应中牵涉到NSMASE2衍生的CER 心肌细胞（CMS），并表明NSMase2活性的体内损失可保护DOX诱导的发作心脏功能障碍和损害。至关重要的是，NSMASE2对于体外和体内抗 - DOX对乳腺癌的癌症影响。基于这些数据，中心假设是NSMase2- 神经酰胺途径对于DOX诱导的心脏毒性至关重要，但对于DOX诱导的抗癌者来说是必不可少的活动。我们提出了三个具体目标：第一个目标将建立DOX诱导的NSMase2-的激活心脏细胞和组织中的CER途径结合体外和体内方法以建立NSMase2 CMS作为DOX诱导的CER产生的主要途径。第二个目标将定义 NSMASE2-CER途径在使用体外和体内损失的介导DOX诱导的心脏毒性中的作用在CMS中建立NSMASE2作为DOX诱导CM细胞死亡和心脏的介体的功能方法纤维化。第三个目标将确定NSMASE2抑制剂作为心脏保护的治疗潜力不使用乳腺合成异种移植模型不干扰DOX的抗癌活性的药物癌症证明NSMASE2抑制剂作为不干扰的心脏保护剂的功效 DOX减少肿瘤生长和转移。总体而言，这些研究将为您提供新的见解 DOX诱导的心脏毒性的发病机理，并建立NSMASE2作为一种新型的可吸毒目标心脏保护。这将为NSMASE2抑制剂作为新颖的发展提供合理的基础心脏保护剂。