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Cruciferous Dithiolethiones for Chronic Heart Failure: Signaling Mechanisms

十字花科二硫代硫酮治疗慢性心力衰竭：信号机制

基本信息

批准号：
8770355
负责人：
YUNBO LI
金额：
$ 46.94万
依托单位：
CAMPBELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8770355
关键词：
Acute Animal Model Anthracyclines Anti-Inflammatory Agents Anti-inflammatory Antineoplastic Agents Biological Factors Bioluminescence Breast Cancer Patient Cardiac Cardiomyopathies Cardiotoxicity Cardiovascular Diseases Cells Chemical Models Chemoprotective Agent Chemosensitization Chronic Clinical Complementary and alternative medicine Coronary heart disease Development Dexrazoxane Dose Doxorubicin Enzymes Etiology Free Radicals Functional disorder Genes Goals Heart failure In Vitro Inflammatory Injury Intervention Investigation Ions Iron Chelating Agents Knockout Mice Long-Term Effects Malignant Neoplasms Mediating Melanoma Cell Metals Modality Molecular Mus Myocardial Myocardial Ischemia Myocardium Neoplasm Metastasis Oxidation-Reduction Pharmaceutical Preparations Pharmacotherapy Play Process Research Rodent Model Role Series Signal Pathway Signal Transduction Signaling Molecule Stress Therapeutic Thiones Treatment Efficacy Up-Regulation Woman anticancer activity base burden of illness clinically significant cytotoxicity dithiolethione in vivo killings lung melanoma malignant breast neoplasm mouse model novel novel strategies prevent public health relevance therapeutic effectiveness tomography tumor

项目摘要

DESCRIPTION (provided by applicant): Chronic heart failure is a major cardiovascular disease burden. Although coronary heart disease is the chief cause of chronic heart failure, drug therapies, especially anticancer drugs have been increasingly becoming a significant etiology. In this context, the anthracycline agent, doxorubicin (Dox) is one of the most important anticancer drugs with major clinical activity in a wide variety of cancers. The clinical use of Dox is severel limited by its cumulative dose-dependent cardiomyopathy, which is believed to occur via redox metal ion/free radical-mediated mechanisms. The iron-chelating agent, dexrazoxane is currently approved to prevent or reduce Dox-induced chronic heart failure (CHF) in women with metastatic breast cancer. Regardless of the use of dexrazoxane as well as Dox derivates, development of CHF remains a critical clinical problem in cancer patients treated with Dox. Hence, there is an urgent need to develop more effective strategies to protect against Dox-induced CHF without compromising its anticancer activity. Extensive studies show that the cancer therapeutic activity of Dox and its cardiotoxicity occur via distinct mechanisms. Therefore, it is likely to develop mechanistically-based strategies to selectively protect against Dox cardiotoxicity without compromising its anticancer activity. We propose the sustained coordinated upregulation of a wide spectrum of antioxidative/anti-inflammatory (AO/AI) enzymes in myocardium by long-term treatment with cruciferous 3H- 1,2-dithiole-3-thione (D3T) as a highly effective CAM strategy for protecting against Dox-induced CHF and potentiating its antitumor activity, and thereby enhancing the therapeutic efficacy of this widely used anticancer drug. To this end, in this R15 application we will investigate if the sustained coordinated upregulation of myocardial AO/AI enzymes by long-term D3T administration prevents or retards the development of Dox- induced CHF in a mouse model that closely mimics the situations in Dox-treated cancer patients. We will also investigate the role of Nrf2 signaling in the sustained coordinated upregulation of cardiac AO/AI enzymes by long-term treatment with D3T as well as the critical involvement of this signaling pathway in protecting against Dox-induced CHF. Finally, we will determine if this novel cruciferous dithiolethione-based cardioprotective modality potentiates Dox's antitumor activity in a mouse model of B16-F10 melanoma lung metastasis. In view of the crucial role of oxidative and inflammatory stress in heart failure of various etiologie, successful completion of this project will provide not only a novel strategy for protecting against Dox-induced CHF, but also an effective CAM modality for the intervention of CHF resulting from other causes, such as myocardial ischemia as well as other anticancer drugs. In this context, Dox is used as a common chemical model to create CHF for studying the molecular pathophysiology as well as cardioprotective strategies, including natural products.

描述（由申请人提供）：慢性心力衰竭是一种主要的心血管疾病负担。虽然冠心病是慢性心力衰竭的主要病因，但药物治疗，特别是抗癌药物治疗已日益成为一个重要的病因。在此背景下，蒽环类药物阿霉素（Dox）是最重要的抗癌药物之一，在多种癌症中具有主要临床活性。Dox的临床应用受到其累积剂量依赖性心肌病的限制，据信其通过氧化还原金属离子/自由基介导的机制发生。铁螯合剂右雷佐生目前被批准用于预防或减少转移性乳腺癌女性中Dox诱导的慢性心力衰竭（CHF）。无论使用右雷佐生以及Dox衍生物，CHF的发展仍然是用Dox治疗的癌症患者中的关键临床问题。因此，迫切需要开发更有效的策略来防止Dox诱导的CHF而不损害其抗癌活性。广泛的研究表明，Dox的癌症治疗活性及其心脏毒性通过不同的机制发生。因此，有可能开发基于机制的策略来选择性地保护Dox心脏毒性而不损害其抗癌活性。我们提出了持续协调上调广谱抗氧化/抗炎（AO/AI）酶在心肌中的长期治疗与十字花科3 H-1，2-二硫杂环戊烯-3-烯（D3 T）作为一种高效的CAM策略，保护免受Dox诱导的CHF和增强其抗肿瘤活性，从而提高这种广泛使用的抗癌药物的治疗效果。为此，在该R15申请中，我们将研究通过长期D3 T施用的心肌AO/AI酶的持续协调上调是否预防或延缓小鼠模型中Dox诱导的CHF的发展，所述小鼠模型密切模拟Dox治疗的癌症患者中的情况。我们还将研究Nrf 2信号传导在D3 T长期治疗心脏AO/AI酶持续协调上调中的作用，以及该信号传导通路在保护免受Dox诱导的CHF中的关键参与。最后，我们将确定这种新的基于十字花科二硫杂环戊硫酮的心脏保护方式是否增强了Dox在B16-F10黑色素瘤肺转移小鼠模型中的抗肿瘤活性。鉴于氧化应激和炎症应激在各种病因的心力衰竭中的关键作用，该项目的成功完成不仅将提供一种新的预防心力衰竭的策略， Dox诱导的CHF，也是一种有效的CAM模式，用于干预由其他原因引起的CHF，如心肌缺血以及其他抗癌药物。在这种情况下，Dox被用作一种常见的化学模型来创建CHF，用于研究分子病理生理学以及心脏保护策略，包括天然产物。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Innovative Bioluminometric Quantification of Cancer Cell Load in Target Organs: Implications for Studying Anticancer Drugs, Including ROS Enhancers.

靶器官中癌细胞负荷的创新生物发光定量：对研究抗癌药物（包括 ROS 增强剂）的启示。

DOI：
10.20455/ros.2016.819
发表时间：
2016
期刊：
Reactive oxygen species (Apex, N.C.)
影响因子：
0
作者：
Zhu,Hong;Kauffman,MeganE;Li,JasonZ;Sarkar,Soumyadeep;Trush,MichaelA;Jia,Zhenquan;Li,YRobert
通讯作者：
Li,YRobert

In Vivo Bioluminescence Imaging of Nuclear Factor kappaB Activation: A Valuable Model for Studying Inflammatory and Oxidative Stress in Live Mice.

核因子 kappaB 激活的体内生物发光成像：研究活小鼠炎症和氧化应激的有价值的模型。